The alarmin cytokines thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are epithelial cell-derived mediators that contribute to the pathobiology and pathophysiology of asthma. Released from airway epithelial cells exposed to environmental triggers, the alarmins drive airway inflammation through the release of predominantly T2 cytokines from multiple effector cells. The upstream positioning of the alarmins is an attractive pharmacological target to block multiple T2 pathways important in asthma. Blocking the function of TSLP inhibits allergen-induced responses including bronchoconstriction, airway hyperresponsiveness, and inflammation, and subsequent clinical trials of an anti-TSLP monoclonal antibody, tezepelumab, in asthma patients demonstrated improvements in lung function, airway responsiveness, inflammation, and importantly, a reduction in the rate of exacerbations. Notably, these improvements were observed in patients with T2-high and with T2-low asthma. Clinical trials blocking IL-33 and its receptor ST2 have also shown improvements in lung function and exacerbation rates; however, the impact of blocking the IL-33/ST2 axis in T2-high versus T2-low asthma is unclear. To date, there is no evidence that IL-25 blockade is beneficial in asthma. Despite the considerable overlap in the cellular functions of IL-25, IL-33, and TSLP, they appear to have distinct roles in the immunopathology of asthma.

1 INTRODUCTION

The epithelial cell-derived alarmins thymic stromal lymphopoietin (TSLP), interleukin (IL)-33, and IL-25 are pleiotropic cytokines found to regulate infection, inflammation, and metabolic homeostasis. They play important roles in many diseases including cancer, allergic and immune-mediated diseases, and diseases of the central nervous system^1-7; however, clinical trials blocking TSLP, IL-33, and IL-25 have mostly been conducted in diseases driven by type 2 (T2) inflammation, and most extensively in patients with asthma. The alarmin cytokines have emerged as key players in asthma pathogenesis, driving T2 cytokines, most notably IL-4, IL-5 and IL-13, from multiple effector cells.^8-10 T2 cytokine expression initiates allergic mechanisms including eosinophilic inflammation, immunoglobulin E (IgE) class switching, B-cell growth, and goblet cell metaplasia.¹¹ Randomized controlled trials (RCTs) have evaluated the efficacy of anti-alarmin monoclonal antibody (mAb) therapies for the treatment of asthma. This review will focus on the immunopathogenic role of alarmins in asthma, and their unique contribution to asthma pathophysiology as evidenced by alarmin-targeted drugs in clinical trials.

2 ALARMIN EXPRESSION AND ASTHMA

Airway epithelial cells (AECs) represent the first line of host defense against environmental pathogens and serve as a major source of alarmins IL-25, IL-33, and TSLP. Alarmins are constitutively expressed in AECs and released following activation of transmembrane pattern recognition receptors (PRRs) including toll-like receptors (TLR) 1, 2, 4-6 and 10, C-type lectin receptors (CLRs) such as dectin-1, mannose receptors (MRs), and protease-activated receptors (PARs) such as PAR-2. TLRs 3, 7-9 and other PRRs are found intracellularly on organelle membranes (e.g., endosomes), and CLRs including MRs and dendritic cell-specific ICAM-3 (DC-SIGN) are also present intracellularly (Figure 1).^{2, 12, 13} Innate immune cells, adaptive immune cells, and structural cells are also capable of releasing alarmins; however, the mechanisms are not well-understood yet.

Details are in the caption following the image — **FIGURE 1**
Open in figure viewer PowerPoint

Release mechanisms of airway epithelial cell-derived alarmins. Immune responses in AEC are initiated through PRR recognition of highly conserved motifs of invading pathogens including lipopolysaccharides, peptidoglycans, viral DNA, and bacterial flagellin. For example, in allergic asthmatic airways, Der p2, a sensitizing protein of house dust mite allergen, activates TLR-4 to release epithelial-derived alarmins ultimately driving type 2 airway inflammation. CLRs (e.g., dectin-1 and MRs) recognize allergen carbohydrate motifs causing alarmin secretion from AEC. Allergen-derived serine proteases activate PAR-2 receptors causing alarmin release from AEC, and they also target the protease sensor region of IL-33 generating a hyperactive shorter IL-33 isoform with 30-60X the biological activity of IL-33_FL. Airway epithelial cell = AEC; C-type lectin receptor = CLR; full-length IL-33 = IL-33_FL; mannose receptors = MR; nucleotide-binding oligomerization domain (NOD)-like receptors = NLR; Pattern recognition receptor = PRR; pathogen-associated molecular pattern = PAMP; protease-activated receptors = PAR; retinoic acid-inducible gene-I (RIG-I)-like receptors = RLR; Toll-like receptor = TLR.

TSLP, a member of the IL-2 family of cytokines, was initially identified as a pre-B-cell growth factor.¹⁴ The TSLP receptor heterodimer consisting of TSLPR and IL-7Rα is broadly expressed within a wide variety of hematopoietic cell populations.^14-22 In response to exogenous and endogenous danger signals, epithelial cells at barrier surfaces as well as immune cells secrete TSLP,^23-32 which promotes T2 inflammation through activation of myeloid dendritic cells (DC), type 2 innate lymphoid cells (ILC2s) and polarization of naïve T helper (Th) cells to Th2 cells.^15-19

IL-33 a member of the IL-1 cytokine family mediates early immune development and polarization toward T2 inflammation.^{33, 34} IL-33 is constitutively expressed in the nuclei of epithelial and vascular endothelial cells and other structural cells exposed to the environment^35-38 and immune cells; murine models show that innate immune cells such as macrophages and mast cells are important producers of IL-33 that contribute to ILC2 activation.^{39, 40} Damage to bronchial epithelial cells at mucosal barrier interfaces by allergen-associated protease activity, pollutants, viral and fungal pathogens leads to further increases in IL-33 release, which serves as a damage-associated molecular pattern (DAMP) signal.^{41, 42} In murine models, epithelial cells exposed to fungal allergens show extracellular accumulation of ATP, activation of P2 purinergic receptors and increases in intracellular Ca²⁺ levels driving the IL-33 secretion signaling cascade.⁴² This, however, remains to be fully described in human cells as quantification is complicated by rapid posttranslational modifications that reduce IL-33 levels.⁴¹

Two isoforms of IL-33 are described, a full-length and a processed form, which are both upregulated during airway inflammatory responses.⁴¹ IL-33 is active in its full-length form and passively released while cleavage of the N-terminal by the inflammasome complex and caspases-1, −3, and −7 inactivates this isoform.⁴¹ When oxidized, IL-33 undergoes a rapid conformational change forming two disulfide bonds that convert IL-33 to an inactive form Additionally, IL-33 is sensitive to serine protease activity exhibited by fungi (Aspergillus fumigatus), allergens such as house dust mite (Dermatophagoides pteronyssinus) and released by mast cells, eosinophils, and Th2 cells that cleave IL-33 in the sensor domain.^{41, 43} The shorter isoform exhibits increased affinity for the IL-33 receptor; additionally, neutrophil proteases enhance IL-33 activity in virally induced exacerbations of asthma.⁴¹ Thus oxidation and proteolytic cleavage are potentially major players in regulating IL-33 activity.

A rare genetic variant of the IL-33 gene has been described that prevents the formation of bio-active splice variants of lL-33. Subjects who carry this rare allele have a 40% lower IL-33 expression and a 50% reduction in asthma risk. As such, amino acids 66–111 on IL-33 are an important functional domain, and interference with IL-33 cleavage may be a useful strategy to reduce IL-33–mediated responses in asthmatic conditions.⁴⁴ Furthermore, a report of a patient with a rare chromosomal duplication encompassing the entire IL-33 gene is described as having many atopic disease manifestations including elevated IgE, hypereosinophilia, eosinophilic skin infiltrations, food allergy, and mild asthma, demonstrating for the first time the effects of IL-33 overexpression in humans.⁴⁵

IL-33 binds to a membrane-bound heteromeric receptor consisting of ST2 (IL-1RL1) and its coreceptor IL-1 receptor accessory protein (IL1RAcP). ST2 is predominantly expressed by CD4⁺ and CD8⁺ T cells, mast cells, ILC2s, macrophages, eosinophils, dendritic cells, basophils, natural killer (NK) T cells, and NK cells.⁴² Under basal conditions, ST2 expression has been observed in subsets of CD4⁺Foxp3⁺ Tregs in the lung.⁴¹ IL-33 induces expression of the epidermal growth factor-like molecule amphiregulin (AREG) in Tregs, promoting immune regulation.⁴² IL-33 also indirectly regulates Tregs by inducing IL-2 production by ILC2s, DCs, or mast cells, that subsequently promote Treg expansion. Therefore, IL-33 can both promote or regulate CD4⁺ T cell immunity depending on the tissue microenvironmental cues.

A soluble form of ST2 (sST2) may function as a decoy receptor.⁴⁶ IL-33 and ST2 levels are markedly increased in the sputum of eosinophilic asthmatics⁴⁷ and in those experiencing acute exacerbations.^48-50 IL-33 is one of the earliest cytokines released in response to inhaled allergens in patients with allergic asthma and is elevated in lung epithelium,³⁵ airway smooth muscle,⁴⁹ and bronchoalveolar lavage,⁵¹ correlating positively with asthma disease severity.³⁶

IL-25 (also known as IL-17 E) is a member of the IL-17 family but has distinct biological effects compared with the rest of the IL-17 family.^{52, 53} IL-25 is preformed and stored in the cytoplasm of airway epithelial cells. Other IL-25-secreting cells include endothelial cells, activated Th2 cells, alveolar macrophages, eosinophils, basophils, bone marrow–derived mast cells, and fibroblasts.^54-60 The IL-25 receptor is a disulphide-linked dimer comprised IL-17Rα and IL-17Rβ subunits⁶¹ and expressed mainly on innate immune cells.^62-69 IL-17Rβ expression is increased on myeloid and plasmacytoid DCs in blood and sputum of allergic asthmatic patients postallergen challenge, and IL-25 stimulation mediates TLR9 expression on plasmacytoid DCs suggesting a potential additional role in aeroallergen-induced immune responses in asthma.⁶³ IL-25 directly augments T2 cytokine production by TSLP-DC-activated Th2 memory cells, by enhancing the production of Th2 transcription factors in an IL-4-independent manner.⁵⁴

Together, the epithelial cell alarmins present an effective defense against pathogens encountering the airway mucosal surface; however, when dysregulated, they can orchestrate immune cell functions that drive pathological responses in the asthmatic airways leading to clinical sequelae (Figure 2).

3 CLINICAL TRIALS OF ANTI-ALARMINS IN ASTHMA

Clinical models have demonstrated a role for the alarmins in the pathogenesis of allergic asthma.^{27, 70-72} This hypothesis was initially tested using a mAb, AMG157 (now known as tezepelumab), which binds to TSLP preventing engagement with its receptor.⁷³ The double-blind, randomized study examined mild, allergic asthmatic subjects challenged with an inhaled allergen known to induce both an early asthmatic response (EAR), a late asthmatic response (LAR), eosinophilic airway inflammation and airway hyperresponsiveness (AHR) to inhaled methacholine (Figure 3). The participants had evidence of baseline T2 airway inflammation, with elevated blood eosinophils, sputum eosinophils, and exhaled nitric oxide (FeNO). Treatment with AMG157 normalized these biomarkers after the first dose, indicating that constitutive release of TSLP is necessary for the maintenance of T2 inflammatory biomarkers in these mild asthmatic subjects. In addition, treatment with AMG157 significantly attenuated the allergen-induced EAR, LAR, sputum eosinophilia, and methacholine AHR.

These results were, in part, replicated in another study using an inhaled antibody fragment, which also binds TSLP (CSJ117; ecleralimab).^{74, 75} Using a similar design, CSJ117 significantly attenuated allergen-induced bronchoconstrictor responses and airway inflammation. Collectively, these results demonstrate that inhaled allergens induce the release of TSLP, presumably from the airway epithelium, which can then drive, at least in part, allergen-induced inflammatory and bronchoconstrictor responses, as well as increased AHR. IL-25 and IL-33 have not yet been carefully investigated in a similar model of allergic asthma.

4 ASTHMA EXACERBATION

Outcomes in asthma clinical trials include assessments of asthma control, forced expiratory volume (FEV₁), quality of life, and frequency of severe asthma exacerbations. It is widely accepted that reducing the risk of asthma exacerbations is the most important of these. Exacerbations are the time of risk in terms of asthma-related mortality; have significant impacts on patients and their families; are associated with loss of time at work or at school; and are costly to the health care system, especially when patients need hospitalization or intensive care management. Asthma exacerbations are frequent occurrences, with even patients with the mildest asthma at risk.⁷⁶ Exacerbations are driven by viral and bacterial infections, and environmental allergen exposures.⁷⁷ Patients with severe asthma can experience two or more exacerbations per year, and this can lead to progressive loss of lung function.⁷⁸ Frequency of exacerbations is reduced but not fully prevented with inhaled corticosteroid (ICS) ± long-acting β₂-agonists (LABA), hence the need for therapies providing additional protection.⁷⁹ All the currently approved biological therapies for asthma have used severe exacerbation frequency as the primary outcome variable for their pivotal clinical trials; significant reduction is demonstrated by blocking IgE,⁸⁰ TSLP,^{81, 82} or IL-5 or IL-4/IL-13 pathways,^83-89 and it is widely recognized that patients with higher blood eosinophil counts respond best to these biologics.^{90, 91} The alarmins are an attractive target for preventing exacerbations, acting upstream of T2 cytokines and triggering a broad range of proinflammatory processes that are orchestrated through dendritic cells and key effector cells that drive eosinophilia.

4.1 Mechanism of TSLP in exacerbations

Clinical trials targeting IL-5 and IL-13 pathways have provided irrevocable evidence that T2 cytokines, at least in part, drive asthma exacerbations.^83-89 TSLP, located upstream in the inflammatory cascade, plays a key role in the induction of T2 responses by stimulating myeloid DC maturation and upregulation of MHC class II, and the co-stimulatory molecules CD40, CD86, CD54, CD80 CD83 and CD-LMAP²⁰ (Figure 4). In turn, TSLP-primed DCs promote the upregulation of OX40L on naïve T cells driving an inflammatory T2 phenotype that secretes IL-4, IL-5, IL-13, and TNFα but not IL-10.⁹² TSLP can also induce DC production of chemokines that induce recruitment of Th2 cells, eosinophils and neutrophils to the inflamed airways,^{27, 93, 94} and primes DCs to induce the expansion and functionality of CRTH2⁺ CD4⁺ Th2 memory cells, driving differentiation of Tregs and hindering developments of FOXP3⁺ Tregs.^95-97 Although CD4⁺ and CD8⁺ T cells do not directly respond to TSLP under resting conditions, TSLPR surface expression increases on these cells following activation,⁹⁸ facilitating TSLP signaling and TCR stimulation to promote proliferation and differentiation to Th2 cells.^{70, 99, 100} TSLP directly supports B-cell lymphopoiesis^{101, 102} from multilineage-committed CD34⁺ progenitor cells¹⁰³ and suppresses the production of IL-10 by pulmonary Tregs¹⁰⁴ altogether maintaining a T2 inflammatory airway environment that is conducive to exacerbating asthma.

In some preclinical asthma models, TSLP drives a predominant ILC2-driven airway inflammatory response.¹⁰⁵ This is also observed in severe asthmatics where increased airway levels of TSLP alone or with TL1A have been shown to mediate the corticosteroid insensitivity of airway ILC2s.¹⁰⁶ In murine models, TSLP, IL-33, and IL-25 signaling reciprocally enhance each other's receptor protein expression on lung ILC2s, enhancing ILC2 activation, and possibly driving ILC2 plasticity.^{107, 108}

4.2 Anti-TSLP and exacerbation outcomes in clinical trials

The most compelling data regarding the clinical efficacy of anti-alarmin therapies come from the phase 3 Navigator study evaluating the anti-TSLP mAb tezepelumab, administered at a dose of 210 mg subcutaneously (sc) q4wk for 52 weeks. In this study of 1061 patients with severe, uncontrolled asthma and at least two asthma exacerbations in the past 12 months, tezepelumab substantially and significantly reduced the annualized asthma exacerbations rate (AAER) and lengthened the time to first exacerbation.¹⁰⁹ Moreover, this reduction in AAER was maintained even in patients with low baseline blood eosinophil counts of <150 cells/μl. Patients receiving tezepelumab also had significantly better asthma control and health-related quality of life (HRQOL); while improvements in asthma control questionnaire (ACQ)-6 and asthma quality of life questionnaire (AQLQ) scores were statistically significant, these aggregate changes did not meet the minimal clinically important difference for these patient-reported outcome measures.

The Navigator study data lend credence to earlier publications reporting on the Pathway study, a phase 2b double-blind study of tezepelumab administered at 70 mg and 210 mg sc q4wks; 280 mg sc q2wks versus placebo for 52 weeks in 550 asthmatics not controlled by high doses ICS + LABA. This study reported a >50% reduction in AAER, and improvements in most other endpoints measured.⁸¹ These results are similar, and perhaps slightly better than other mAb intervention studies using anti-IL-5, anti-IL-5R, and anti-IL-4Rα,^{83, 85, 88} all of which are now approved for the management of severe asthma; however, no head-to-head comparisons are available. The reduction in AAER was similar in participants with blood eosinophils above and below 250 cells/μl and in those defined as T2 high and T2 low. Although AAER differed by season, tezepelumab reduced AAER across all seasons.¹¹⁰ Furthermore, evaluating the effect of tezepelumab in severe uncontrolled asthma with perennial allergy over a full year, including periods of seasonal allergies, showed the improvement in exacerbation rate was comparable in patients with and without perennial allergy, including those patients meeting or not meeting eligibility criteria for the anti-IgE biologic omalizumab.¹¹¹ Interestingly, a higher reduction in exacerbation (84%) in those with 3 or more allergen reactivities demonstrates a clear positive effect in T2 asthma and effectiveness in the presence of allergy. Additional post-hoc evaluations of these data demonstrated a comparable effect of tezepelumab in patients with and without self-reported nasal polyps¹¹² suggesting, again, that tezepelumab may work in a wider range of subjects.

4.3 Mechanism of IL-33 in exacerbations

Like TSLP, IL-33 plays a central role in activating both the innate and adaptive arms of immunity. IL-33 can activate resident DC to mature and induce differentiation of T cells into Th2 polarized cells^{9, 113, 114} and promote naïve CD4⁺ T cells to produce IL-5 and IL-3,³³ which in turn stimulates eosinophil survival, adhesion, and degranulation.¹¹⁵ IL-33-activated DCs also promote mast cell survival, adhesion, and increased cytokine production and alveolar macrophage-mediated secretion of IL-13 (Figure 4).^{116, 117} Macrophages express both the membrane-bound ST2 and sST2 and upon IL-33 stimulation are either activated to promote M1 chemokine generation (CCL3) in naïve macrophages or to enhance the expression of M2 chemokine markers (CCL17, CCL18, CCL24) in previously polarized macrophages.^{117, 118} IL-33 is also a potent activator of ILC2s, upregulating the co-stimulatory molecules OX40L and PD-L1 and inducing T2 cytokine production,^{119, 120} including up to 100-fold more IL-5 and IL-13 compared with activated Th2 cells.¹²¹ IL-33 also regulates IL17A and IL-31 secretion indicating a role for IL-33/ST2 axis in Th2/IL-31 and Th17 immune responses.¹²²

IL-33 also plays a role in initiating the adaptive response. Memory Th2 cells express higher levels of ST2 than effector Th2 cells and IL-33 induces the expression of IL-4, IL-5, and IL-13 in both.^{123, 124} Additionally, IL-33 can initiate IL-9 secretion from CD4⁺ T cells.¹²⁵ These functions of IL-33 collectively drive T2 inflammation in a multifactorial manner. Larger clinical trials will be needed to determine whether IL-33 blockade indeed performs better in patients with low blood eosinophil levels, as this finding is somewhat counterintuitive in the context of IL-33 biology.

Rhinoviruses are major players in asthma exacerbations in both children and adults.^{126, 127} In models of viral-induced asthma exacerbations using mice infected with influenza virus or human cells exposed to rhinovirus-16, type II alveolar cells in mice and bronchial ciliated cells in human subjects were a major source of IL-33.¹²⁶ Exacerbations characterized by increased airway hyperresponsiveness and T2 inflammatory response were inhibited by blocking ST2, highlighted a role for IL-33, and not TSLP.¹²⁶ In addition, using a human exposure model of viral infection IL-33 induced type 2 cytokine generation by ILC2s during rhinovirus-induced asthma exacerbation.¹²⁷ Additionally, IL-33 dampened both innate and adaptive type 1 inflammatory responses¹²⁶ by causing epithelial and dendritic cells of mice to decrease IFN-β expression. Together, these data highlight the potential of therapies targeting the IL-33/ST2 axis for treating viral-induced asthma exacerbations.

4.4 IL-33 pathway and exacerbation outcomes in clinical trials

Recent clinical trials blocking components of the IL-33/ST2 axis have examined the effects on asthma exacerbations. In patients with moderate-to-severe asthma (GINA step 4–5) for at least 12 months, the anti-IL-33 mAb, itepekimab was administered over a 12-week period, alone at 300 mg sc q2wks, or together with the anti-IL4Rα mAb dupilumab 300 mg sc q2wks versus placebo.¹²⁸ The study used a medication withdrawal study design, where treatments with LABAs were discontinued at week 4, and ICS tapered at weeks 6 through 9. At week 12, itepekimab significantly improved asthma control, an effect similar to that seen with dupilumab. Compared with dupilumab alone and the combination itepekimab plus dupilumab, the odds ratio for itepekimab was lowest in the <300 eosinophils/μl subgroup (0.46), and highest in the ≥300 eosinophils/μl subgroup (0.39), with the combination itepekimab plus dupilumab not as good as either treatment alone for asthma control. Itepekimab and dupilumab monotherapies significantly improved pre-bronchodilator FEV1 versus placebo by 0.14 L and 0.16 L, respectively. Itepekimab demonstrated the largest improvement (0.06 L vs 0.02 L for the other treatment groups) in the <300 eosinophils/μl subgroup, and monotherapies dupilumab and itepekimab showed significant improvements (0.30 L and 0.18 L, respectively, and 0.15 L for combination) in the ≥300 eosinophils/μl subgroup. Other endpoints ACQ-5 and AQLQ(S) improved to a similar degree in all active treatment groups, and T2 biomarkers including FeNO and serum IgE, eotaxin, and periostin were reduced by itepekimab, but the effect was generally less than that of duplilumab or combination therapy.

Astegolimab, a human ST2 mAb was studied at three doses (70 mg, 210 mg, 490 mg) sc q4wk for 52wks versus placebo in 502 patients with severe asthma. Overall, lower and higher doses significantly reduced AAER by 37% and 42%, respectively, with no significant improvement (22%) observed at the mid-range dose.¹²⁹ Moreover, when the patients were stratified by eosinophil subgroups with cutoffs at 300 cells/μl and 150 cells/μl, the reduced AAER was still only seen at the lower and higher doses; in patients with eosinophil counts <300 cells/μl the AAER reduction was 35% and 54%, respectively; in patients with eosinophil counts ≥150 cells/μl the AAER reduction was 42% for both lower and higher doses. At the 210 mg dose, there was no significant AAER reduction overall or in any eosinophil subgroups. These results suggest that astegolimab, unlike tezepelumab, may be of lesser benefit in patients characterized as having a T2-high asthma phenotype. It is intriguing that there was no dose response for exacerbations and no effect in patients with eosinophils >300 cells/μl, although this might simply reflect the small sample size. Further confirmatory phase 3 randomized controlled trials blocking IL-33 and ST2 in patients with severe asthma are warranted.

5 LUNG FUNCTION

Variable bronchoconstriction is a hallmark of asthma, with inflammation contributing to persistent airflow obstruction in part due to irreversible remodeling of the airway wall.¹³⁰ Periods of intense airway inflammation during asthma exacerbations are associated with a decline in lung function.⁷⁸

5.1 Mechanisms of alarmins in lung function and AHR

The alarmin cytokines are believed to contribute to bronchoconstriction and airway remodeling (Figure 5). TSLP and IL-33 induce expression of smooth muscle actin, collagen, and fibronectin^{131, 132} Airway smooth muscle (ASM) cell proliferation and expression of IL-6, IL-8, and eotaxin-1 is mediated by TSLP.^{133, 134} Stimulation with IL-25 can modulate bronchial airway smooth muscle hyperplasia and collagen deposition leading to airway remodeling,¹³⁵ and is reflected in asthmatic patients with high IL-25 transcripts having greater AHR than those with low transcript levels.¹³⁶

Alarmins act upstream of cellular pathways that ultimately trigger the release of mediators of bronchoconstriction. TSLP stimulation of mast cells induces the release of T2 cytokines including IL-5 and IL-13.^{24, 137} Basophils are a significant source of TSLP¹⁶ and express high levels of TSLPR^{16, 138}; overnight incubation of basophils with TSLP upregulates epithelial alarmin cytokine receptor expression (TSLPR, IL-25R, ST2), activation markers (CD203c), T2 cytokines (IL-4, IL-13) and enhances degranulation of histamine.¹³⁸ In mice, TSLP promotes bone-marrow-resident precursor cells to differentiate into basophils independently of IL-3.^{16, 139} This axis is not yet fully elucidated in humans and warrants further study. IL-33 promotes basophil IgE-dependent and IgE-independent release of histamine and secretion of IL-4, IL-5, IL-6, IL-8, IL-9, IL-13, CCL2 and CCL3.^{125, 140-142} IL-33 also induces basophil CD11b expression, adhesion, and primes eotaxin-induced migration.^{143, 144} IL-33 also induces production of IL-13 from mast cells.¹⁴⁵ IL-25 inhibits basophil apoptosis and augments IgE-mediated basophil degranulation, but has no effect on inflammatory cytokine release.⁶⁶ Mast cells are shown to express equal levels of IL-25R to those of eosinophils, T cells, and endothelial cells⁵⁸; however, the effect of IL-25 stimulation of mast cells has not been reported.

5.2 Anti-TSLP and measures of airway hyperresponsiveness in clinical trials

AHR is a cardinal feature of asthma and is measured by increased bronchoconstrictor responses to inhaled direct-acting stimuli, such as methacholine,¹⁴⁶ or inhaled indirect-acting stimuli, such as mannitol.¹⁴⁷ AHR is not regularly tested in large clinical trials of severe asthma patients. A small mechanistic study in mild allergic asthmatics reported a significant 1.24 doubling dose (dd) improvement in methacholine PC₂₀ after treatment with tezepelumab 700 mg IV q4wks for 12 weeks, versus 0.66 with placebo.⁷³ Moreover, two recent publications examined the effect of tezepelumab treatment on AHR to mannitol in asthmatic patients. Treatment with tezepelumab for 28 weeks in a subgroup of patients with moderate-to-severe asthma significantly improved mannitol PD₁₅ by 1.41 dd versus 0.57 dd with placebo¹⁴⁸ although the lung function of some patients may have been lower than that recommended for mannitol challenge. In 40 mild–moderate asthmatics, treatment with tezepelumab for 12 weeks improved mannitol PD₁₅ by 1.9 dd versus 1.0 dd in placebo (p = 0.06) at 4 weeks after the last dose, and this benefit was maintained 13 weeks after the last dose.¹⁴⁹ In both mannitol investigations, dose shift magnitude is likely limited by methodology with the top dose of 635 mg. Both studies also reported a greater proportion of negative mannitol responders after treatment, thereby supporting the potential underestimation of a dose shift endpoint. The improvement in AHR was greater in those with eosinophilic asthma. Together, these studies validate the initial proof-of-concept publication by Gauvreau and colleagues that identified tezepelumab as a potentially effective asthma treatment.⁷³ To date, the effect of IL-25 and IL-33 blockade on AHR has not been evaluated.

5.3 Anti-TSLP and measures of lung function in clinical trials

In small studies of patients with mild asthma and nearly normal lung function, it is not surprising that tezepelumab does not improve baseline FEF_25-75%¹⁴⁹ or FEV₁.⁷³ As discussed earlier, in mild allergic asthmatic patients undergoing allergen bronchoprovocation, the early and late bronchoconstriction responses significantly improved by 28% and 45%, respectively, after 12 weeks tezepelumab 700 mg IV q4wks,¹⁵⁰ and 17% and 48%, respectively, after 12 weeks CSJ117 4 mg inhaled once daily.^{74, 75} In both studies inhibition of allergen-induced bronchoconstriction was accompanied by a major reduction in sputum eosinophils that did not correlate to the inhibition of the attenuation of fall in FEV₁, suggesting that other cells, such as mast cells may be driving changes in lung function.

Treatment with the anti-TSLP mAb tezepelumab has consistently improved lung function. The Pathway study, conducted in patients selected for having reversible airflow obstruction and resting bronchoconstriction, demonstrated that tezepelumab improved pre-bronchodilator FEV₁ by 120–150 ml greater than placebo, and this improvement was observed by the first measurement at week 4.⁸¹ When patients were stratified by sensitivity to perennial aeroallergen, the improvement in pre-bronchodilator FEV₁ was found to be independent of allergy status.¹¹¹ Similar improvements were reported in the Navigator study where patients with reversible airflow obstruction and resting bronchoconstriction randomized to tezepelumab experienced pre-bronchodilator FEV₁ improvement 130 ml greater than placebo after 52-week treatment; improvements were seen by the first measurement at 2 weeks.¹⁰⁹ Stratified by blood eosinophil counts, there were smaller improvements versus placebo seen in those with eosinophils <150 cells/μl (30 ml), compared to those with eosinophils >150 cells/μl (170 ml). The effect of tezepelumab on FEV₁/FVC ratio and postbronchodilator FEV₁ was not reported.

5.4 IL-33 pathway blockade and measures of lung function in clinical trials

Improvements in lung function have also been reported in clinical trials blocking the IL-33/ST2 axis. Treatment with the anti-IL-33 mAb, itepekimab, for 12 weeks in asthmatic patients improved FEV₁ by 140 ml more than placebo. Stratification by eosinophil levels showed FEV₁ improvement was greater in the group with the highest eosinophils (>300 cells/μl).¹²⁸ Similarly, blockade of ST2 with astegolimab for 52wks in asthmatic patients improved FEV₁ by 130 ml compared with 100 ml in the placebo group.¹²⁹ This FEV₁ improvement appeared greater in the high eosinophil group; however, none of these changes was statistically significant. Thus, blockade of IL-33 and ST2 both show some improvement in FEV₁, which is more evident in patients with high eosinophil levels, while astegolimab demonstrated no impact on exacerbation rates in this group, demonstrating a dissociation between the two outcomes.

5.5 IL-25 blockade and measures of lung function in clinical trials

To date, there is no convincing evidence that blocking the IL-25 pathway improves lung function. Brodalumab blocks IL-17RA, inhibiting several IL-17 molecules including IL-17 E (IL-25). In a dose-response study of 12 weeks treatment with brodalumab 140, 210, and 280 mg or placebo sc q2wk, patients with mean FEV₁ 65%, with 20% reversibility were evaluated. The primary endpoint of ACQ had a small but not statistically significant improvement in the high reversibility (>20%) group.¹⁵¹ However, there was no overall effect on ACQ, pre-bronchodilator FEV₁, nor was there any signal in the high reversibility group or trend toward a dose response, which may be a result of the small sample size. To date, no clinical trials have been conducted that specifically block IL-25, or the IL-25 receptor subunit, IL-17RB, which is mainly expressed in cells associated with T2 inflammation.

6 ALARMINS AND INFLAMMATORY BIOMARKERS

TSLP has a wide complement of direct functions on eosinophils, leading to their accumulation in the airways. TSLP stimulates eosinophil differentiation in human blood and cord blood-derived CD34⁺ cells that express the TSLP receptor and IL-7α chain subunit.^{152, 153} TSLP stimulation of CD34⁺ progenitor cells also causes a dose-dependent release of T2 cytokines, IL-5, IL-13, GM-CSF, as well as chemokines CCL22, CCL17, CXCL8, and CCL1, and increased expression of IL-5Rα.^{150, 153} TSLP stimulation prevents apoptosis of mature eosinophils, upregulates adhesion molecule CD18, intercellular adhesion molecule-1 and induces IL-6, CXCL8, CXCL1, CCL2 cytokine secretion while downregulating L-selectin expression.¹⁵⁴

Several clinical trials have included measures of inflammation as study endpoints. In the Navigator study, tezepelumab reduced blood eosinophils and FeNO at the first measurement at week 2, and this benefit persisted throughout the 52-week treatment period.¹⁰⁹ This suppression of eosinophils largely mimicked results reported from the Pathway study and post-hoc analyses, showing reduction in blood eosinophils and FeNO irrespective of atopic status or season.^{81, 110, 111} Emson et al. reported significant reductions in levels of eosinophils, FeNO, IL-5 and IL-13 by tezepelumab, regardless of nasal polyposis status.¹¹²

Mechanistic studies have been conducted to understand the anti-inflammatory mechanisms of TSLP blockade. The Cascade study demonstrated 28 weeks of treatment of tezepelumab significantly reduced submucosal eosinophils compared with placebo and irrespective of T2 status at baseline. However, the number of neutrophils, CD3⁺ T cells, CD4⁺ T cells, tryptase+ mast cells, and chymase+ mast cells and indicators of airway remodeling as measured by the change in reticular basement membrane thickness and epithelial integrity were not reduced by tezepelumab treatment, suggesting that improvements in clinical outcomes are likely a reflection of reduced airway eosinophils.¹⁴⁸ In a study by Sverrild and colleagues, 12 weeks of treatment with tezepelumab significantly decreased airway tissue and BAL eosinophils by 74% and 75%, respectively,¹⁴⁹ and reduced mast cell numbers by 25%, which reached statistical significance in a subpopulation of eosinophilic patients. Mechanistic studies have also been performed in patients with milder disease. Gauvreau et al. reported inhibition of allergen-induced levels of blood and sputum eosinophils, plus an overall reduction in baseline FeNO by 1 week and blood eosinophils by 1 month,⁷³ suggesting constitutive TSLP production in airways drives a low level of T2 inflammation in mild disease. Another allergen bronchoprovocation study examining an inhaled anti-TSLP fragment, CSJ117, reported similar reductions in FeNO and allergen-induced sputum eosinophils⁷⁴ without reducing systemic eosinophilia, reflecting the local delivery of drug, and providing evidence that blocking TSLP in the lungs alone may provide adequate protection from environmental allergens.

Similar to TSLP, IL-33 also has direct effects on eosinophils. IL-33 induces CD11b expression, adhesion to albumin, fibronectin, ICAM-1, and VCAM-1, as well as enhancing eosinophil survival and cytokine production.^{47, 143, 155, 156} ST2 is highly expressed in hematopoietic progenitor cells and like TSLP, IL-33 primes the migration to the chemoattractant CXCL12.¹⁵⁷ Although effects of IL-25 blockade on eosinophilic inflammation has not been measured in humans, IL-25 has been shown to have direct effects on eosinophils in vitro by increasing expression of chemokines CCL2 and CCL3,¹⁵⁸ regulating the expression of adhesion molecules ICAM-1, ICAM-3 and L-selectin,⁶⁵ and priming mobilization of eosinophil progenitors to CXCL12.¹⁵⁹

Treatment with the anti-ST2 mAb, astegolimab, led to a substantial and consistent decrease in blood eosinophil counts throughout a 52-week treatment period; however, there was no corresponding improvement in FeNO across any of the doses studied.¹²⁹ In a corticosteroid withdrawal study, the anti-IL-33 mAb itepekimab prevented an increase in blood eosinophils and blunted the increase in FeNO that was observed in the placebo group.¹²⁸

These preliminary studies blocking the IL-33 pathways both show improvement in blood eosinophils without a significant improvement in FeNO, in contrast to tezepelumab, which consistently reduces both, suggesting that despite the many overlapping pathways of TSLP and IL-33, these alarmins drive asthma in different ways¹⁶⁰ (Figure 5) (Table 1).

TABLE 1. Clinical trials evaluating the effect of anti-alarmins in inflammatory allergic diseases

Target	Phase	Patients	Drug	Primary outcome	Result/Status	NCT	Reference
TSLP	1	Mild allergic asthma	AMG 157/MEDI9929/Tezepelumab	Late asthmatic response	Positive	NCT01405963	72
TSLP	1	Moderate–severe AR		TNSS AUC	Positive	NCT02237196	160
TSLP	2	Uncontrolled asthma		Mannitol PC15	Negative	NCT02698501	148
TSLP	2	Uncontrolled asthma		AAER	Positive	NCT02054130	80
TSLP	2	Moderate–severe asthma		Airway submucosal inflammation	Positive	NCT03688074	147
TSLP	2	Moderate–severe AD		EASI	Negative	NCT02525094	161
TSLP	3	Physician diagnosed asthma		AAER	Positive	NCT03347279	81
TSLP	1	Mild allergic asthma	CSJ117	Late asthmatic response	Positive	NCT03138811	73
TSLP	2	Physician diagnosed asthma	CSJ117	FEV1	Terminated	NCT04410523
TSLPR	PC	Non-human primate	RG7258	T2 inflammation	Positive		162
TSLPR	PC	Non-human primate	ASP7266/UPB-101	Skin allergic reaction	Positive		163
TSLPR	1	Mild asthma	ASP7266/UPB-101	Safety	In progress	NCT05448651
IL-33	1	Mild allergic asthma	REGN3500/SAR440340/Itepekumab	Sputum inflammation	Not posted	NCT03112577
IL-33	2	Physician diagnosed asthma	REGN3500/SAR440340/Itepekumab	Loss of asthma control	Positive	NCT03387852	127
IL-33	2	Moderate–severe AD	ANB020/Etokimab	EASI	Negative	NCT03533751
IL-33	2	Chronic rhinosinusitis wNP	ANB020/Etokimab	Nasal Polyp Score	Negative	NCT03614923
IL-33	2	Early-onset uncontrolled asthma	MEDI3506/Tozorakimab	pre-BD FEV1	In progress	NCT04570657
IL-33	2	COPD and chronic bronchitis		pre-BD FEV1	In progress	NCT04631016
IL-33	2	Chronic AD		EASI	In progress	NCT04212169
ST2	1	Chronic rhinosinusitis wNP	RG6149/ MSTT1041A/ AMG282/Astegolimab	Safety	Not posted	NCT02170337
ST2	1	Mild asthma		PK/PD	Not posted	NCT01928368
ST2	2	Severe asthma		AAER	Positive	NCT02918019	128
ST2	2	Moderate–severe AD		EASI	Negative	NCT03747575	164
ST2	2	Severe asthma with AFAD	GSK3772847/Melrilimab	Blood Eosinophils	Positive	NCT03393806
ST2	2	Moderate–severe asthma	GSK3772847/Melrilimab	Loss of asthma control	Not posted	NCT03207243
IL-17RA	2	Moderate–severe asthma	Brodalumab	ACQ composite score	Negative	NCT01902290	150

7 CONCLUSION

Both mechanistic studies and clinical trials in asthmatic patients have emphasized a critical role in the release of TSLP and IL-33, likely from the airway epithelium, and engagement of their receptor complexes in the pathogenesis of asthma. The strongest evidence has been provided by studies with mAbs, which bind to these alarmins and which, in addition to establishing safety, have demonstrated clinically important benefits, particularly in patients with severe asthma. The mAb, which is the most advanced in clinical development, and already approved for clinical use in some countries, is tezepelumab, which not only reduces asthma exacerbation risk, but also improves all other asthma outcomes measured in the clinical trials, including biomarkers of inflammation, and AHR. In contrast to other asthma biologics, which target IL-5, IL-5Rα, or IL-4Rα, tezepelumab has been demonstrated to provide these clinical benefits in severe asthma patients with blood eosinophil counts <150 cells/μl, and who do not have biomarker evidence of T2-high asthma. Another interesting approach to blocking TSLP has been the development of a mAb fragment delivered by inhalation, rather than subcutaneously or intravenously, which has demonstrated clinical benefit in early studies. Interestingly, the effects of these approaches span the range of severity of asthma, from very mild (in the proof-of-concept studies) to severe asthma, characterized by persistent poor asthma control despite standard of care treatment.

Antibodies against IL-33 and its receptor ST2 have also suggested that the IL-33 axis is important in severe asthma. The development of these mAbs is less advanced than for TSLP, but larger clinical trials are underway. The third epithelial alarmin, IL-25 does not have any clinical trial evidence to support a biological role in severe asthma; however, the studies reported with a mAb against its receptor were not sufficiently powered to confidently assess efficacy against asthma outcomes, such as severe exacerbations, where other anti-alarmins have shown benefit.

The recognition that the release of TSLP, and possibly IL-33, is critical to the development of severe asthma exacerbations, and blockade of the alarmins improves all asthma-related clinical outcomes represents a major advance in the understanding of asthma pathogenesis and has resulted in new treatment options to treat severe asthma. Positioning of the alarmin cytokines upstream of the inflammatory cascade targeted by other asthma biologics may be additionally advantageous, but more studies are needed to fully elucidate this potential benefit.

ACKNOWLEDGMENTS

All authors contributed to the content of this manuscript, reviewed, and approved the final version. The authors would like to acknowledge AstraZeneca Canada for financial support in publishing this manuscript.

CONFLICT OF INTEREST

The authors have no conflict of interest related to this manuscript.

Outside of this work, GMG reports receiving consulting or speaker fees from AstraZeneca. Sanofi-Regeneron and research grants from Biohaven, Genentech, BioGaia, Novartis; CB reports receiving consulting or speaker fees from Valeo, AstraZeneca, GSK, Grifols, Takeda, and research grants (clinical trials paid to Vancouver Coastal Health Research Institute/University of British Columbia) from Biohaven, AstraZeneca, Regeneron, GSK, Novartis, Sanofi, Teva; LPB reports receiving consulting or speaker fees from AstraZeneca, Covis, Cipla, GlaxoSmithKline, Novartis, Merck, Sanofi-Regeneron, and research grants from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis, Sanofi-Regeneron, Biohaven; DWC reports receiving research grants from Department of Medicine University of Saskatchewan, AstraZeneca, Biohaven, Novartis, CSACI, and AllerGen NCE; AC reports receiving consulting or speaker fees from AstraZeneca, Covis, Valeo pharma, GlaxoSmithKline, Sanofi-Regeneron, and research grants from GlaxoSmithKline; RL reports receiving consulting or speaker fees from Novartis, AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Valeo Pharma Inc research grants from Biohaven; POB reports personal fees for consulting or speaker fees from AstraZeneca, GSK, Medimmune, Chiesi, Menarini, and Covis and research grants from AstraZeneca, Medimmune, Biohaven, Merck, and Bayer. RL reports receiving consulting or speaker fees from AstraZeneca, GlaxoSmithKline, Regeneron, Sanofi Genzyme and Valeo Pharma Inc. RS reports speaker fees from AstraZeneca, Teva, Genentech and Grants-In Aid from AstraZeneca, GlaxoSmithKline, Teva, Genentech.

REFERENCES

1Liew FY, Girard JP, Turnquist HR. Interleukin-33 in health and disease. Nat Immunol. 2016; 16(11): 676-689.
10.1038/nri.2016.95
CAS Web of Science® Google Scholar
2Borowczyk J, Shutova M, Brembilla NC, Boehncke WH. IL-25 (IL-17 E) in epithelial immunology and pathophysiology. J Allergy Clin Immunol. 2021; 148(1): 40-52. doi:10.1016/j.jaci.2020.12.628
10.1016/j.jaci.2020.12.628
CAS PubMed Web of Science® Google Scholar
3Murdaca G, Greco M, Tonacci A, et al. IL-33/IL-31 Axis in immune-mediated and allergic diseases. Int J Mol Sci. 2019; 20(23): 5856. doi:10.3390/ijms20235856
10.3390/ijms20235856
CAS PubMed Web of Science® Google Scholar
4Shakerian L, Kolahdooz H, Garousi M, et al. IL-33/ST2 axis in autoimmune disease. Cytokine. 2022; 158:156015. doi:10.1016/j.cyto.2022.156015
10.1016/j.cyto.2022.156015
CAS PubMed Web of Science® Google Scholar
5Park JH, Jeong DY, Peyrin-Biroulet L, Eisenhut M, Shin JI. Insight into the role of TSLP in inflammatory bowel diseases. Autoimmun Rev. 2017; 16(1): 55-63. doi:10.1016/j.autrev.2016.09.014
10.1016/j.autrev.2016.09.014
CAS PubMed Web of Science® Google Scholar
6Corren J, Ziegler SF. TSLP: from allergy to cancer. Nat Immunol. 2019; 20(12): 1603-1609. doi:10.1038/s41590-019-0524-9
10.1038/s41590-019-0524-9
CAS PubMed Web of Science® Google Scholar
7Deng C, Peng N, Tang Y, et al. Roles of IL-25 in type 2 inflammation and autoimmune pathogenesis. Front Immunol. 2021; 12:691559. doi:10.3389/fimmu.2021.691559
10.3389/fimmu.2021.691559
CAS PubMed Web of Science® Google Scholar
8Liu Y-J. Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med. 2006; 203(2): 269-273.
10.1084/jem.20051745
PubMed Web of Science® Google Scholar
9Besnard A-G, Togbe D, Guillou N, Erard F, Quesniaux V, Ryffel B. IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur J Immunol. 2011; 41(6): 1675-1686. doi:10.1002/eji.201041033
10.1002/eji.201041033
CAS PubMed Web of Science® Google Scholar
10Xu M, Dong C. IL-25 in allergic inflammation. Immunol Rev. 2017; 278(1): 185-191.
10.1111/imr.12558
CAS PubMed Web of Science® Google Scholar
11Finkelman FD, Hogan SP, Hershey GK, Rothenberg ME, Wills-Karp M. Importance of cytokines in murine allergic airway disease and human asthma. J Immunol. 2010; 184(4): 1663-1674. doi:10.4049/jimmunol.0902185
10.4049/jimmunol.0902185
CAS PubMed Web of Science® Google Scholar
12Ebina-Shibuya R, Leonard WJ. Role of thymic stromal lymphopoietin in allergy and beyond. Nat Rev Immunol. 2022; 1: 1-14. doi:10.1038/s41577-022-00735-y
10.1038/s41577-022-00735-y
Web of Science® Google Scholar
13Cayrol C, Girard JP. Interleukin-33 (IL-33): a critical review of its biology and the mechanisms involved in its release as a potent extracellular cytokine. Cytokine. 2022; 156:155891. doi:10.1016/j.cyto.2022.155891
10.1016/j.cyto.2022.155891
CAS PubMed Web of Science® Google Scholar
14Milford TAM, Su RJ, Francis OL, et al. TSLP or IL-7 provide an IL-7Rα signal that is critical for human B lymphopoiesis. Eur J Immunol. 2016; 46(9): 2155-2161.
10.1002/eji.201646307
CAS PubMed Web of Science® Google Scholar
15Pattarini L, Trichot C, Bogiatzi S, et al. TSLP-activated dendritic cells induce human T follicular helper cell differentiation through OX40-ligand. J Exp Med. 2017; 214(5): 1529-1546.
10.1084/jem.20150402
CAS PubMed Web of Science® Google Scholar
16Siracusa MC, Saenz SA, Hill DA, et al. TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation. Nature. 2011; 477(7363): 229-233. doi:10.1038/nature10329
10.1038/nature10329
CAS PubMed Web of Science® Google Scholar
17Han H, Headley MB, Xu W, Comeau MR, Zhou B, Ziegler SF. Thymic stromal lymphopoietin amplifies the differentiation of alternatively activated macrophages. J Immunol. 2013; 190(3): 904-912.
10.4049/jimmunol.1201808
CAS PubMed Web of Science® Google Scholar
18Wang Q, Du J, Zhu J, Yang X, Zhou B. Thymic stromal lymphopoietin signaling in CD4+ T cells is required for TH2 memory. J Allergy Clin Immunol. 2015; 135(3): 781-791. e3.
10.1016/j.jaci.2014.09.015
CAS PubMed Web of Science® Google Scholar
19Cook EB, Stahl JL, Schwantes EA, Fox KE, Mathur SK. IL-3 and TNFα increase thymic stromal Lymphopoietin receptor (TSLPR) expression on eosinophils and enhance TSLP-stimulated degranulation. Clin Mol Allergy. 2012; 10(1): 1-9.
10.1186/1476-7961-10-8
PubMed Google Scholar
20Froidure A, Shen C, Gras D, Van Snick J, Chanez P, Pilette C. Myeloid dendritic cells are primed in allergic asthma for thymic stromal lymphopoietin-mediated induction of Th2 and Th9 responses. Allergy. 2014; 69(8): 1068-1076.
10.1111/all.12435
CAS PubMed Web of Science® Google Scholar
21Li H, Zhao H, Yu J, et al. Increased prevalence of regulatory T cells in the lung cancer microenvironment: a role of thymic stromal lymphopoietin. Cancer Immunol Immunother. 2011; 60(11): 1587-1596.
10.1007/s00262-011-1059-6
CAS PubMed Web of Science® Google Scholar
22Pandey A, Ozaki K, Baumann H, et al. Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nat Immunol. 2000; 1(1): 59-64.
10.1038/76923
CAS PubMed Web of Science® Google Scholar
23Allahverdian S, Harada N, Singhera GK, Knight DA, Dorscheid DR. Secretion of IL-13 by airway epithelial cells enhances epithelial repair via HB-EGF. Am J Respir Cell Mol Biol. 2008; 38(2): 153-160. doi:10.1165/rcmb.2007-0173OC
10.1165/rcmb.2007-0173OC
CAS PubMed Web of Science® Google Scholar
24Allakhverdi Z, Comeau MR, Jessup HK, et al. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med. 2007; 204(2): 253-258.
10.1084/jem.20062211
CAS PubMed Web of Science® Google Scholar
25Kato A, Xiao H, Chustz RT, Liu MC, Schleimer RP. Local release of B cell–activating factor of the TNF family after segmental allergen challenge of allergic subjects. J Allergy Clin Immunol. 2009; 123(2): 369-375.e2. doi:10.1016/j.jaci.2008.11.022
10.1016/j.jaci.2008.11.022
CAS PubMed Web of Science® Google Scholar
26Vu AT, Baba T, Chen X, et al. Staphylococcus aureus membrane and diacylated lipopeptide induce thymic stromal lymphopoietin in keratinocytes through the toll-like receptor 2-toll-like receptor 6 pathway. J Allergy Clin Immunol. 2010; 126(5): 985-993. e3.
10.1016/j.jaci.2010.09.002
CAS PubMed Web of Science® Google Scholar
27Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP. Nat Immunol. 2002; 3(7): 673-680.
10.1038/ni805
CAS PubMed Web of Science® Google Scholar
28Zhang K, Shan L, Rahman MS, Unruh H, Halayko AJ, Gounni AS. Constitutive and inducible thymic stromal lymphopoietin expression in human airway smooth muscle cells: role in chronic obstructive pulmonary disease. Am J Physiol Lung Cell Mol Physiol. 2007; 293(2): L375-L382.
10.1152/ajplung.00045.2007
CAS PubMed Web of Science® Google Scholar
29Okayama Y, Okumura S, Sagara H, et al. FcϵRI-mediated thymic stromal lymphopoietin production by interleukin-4-primed human mast cells. Eur Respir J. 2009; 34(2): 425-435.
10.1183/09031936.00121008
CAS PubMed Web of Science® Google Scholar
30Allakhverdi Z, Comeau MR, Jessup HK, Delespesse G. Thymic stromal lymphopoietin as a mediator of crosstalk between bronchial smooth muscles and mast cells. J Allergy Clin Immunol. 2009; 123(4): 958-960.e2.
10.1016/j.jaci.2009.01.059
CAS PubMed Web of Science® Google Scholar
31Nomura K, Kojima T, Fuchimoto J, et al. Regulation of interleukin-33 and thymic stromal lymphopoietin in human nasal fibroblasts by proinflammatory cytokines. Laryngoscope. 2012; 122(6): 1185-1192.
10.1002/lary.23261
CAS PubMed Web of Science® Google Scholar
32Kashyap M, Rochman Y, Spolski R, Samsel L, Leonard WJ. Thymic stromal lymphopoietin is produced by dendritic cells. J Immunol. 2011; 187(3): 1207-1211.
10.4049/jimmunol.1100355
CAS PubMed Web of Science® Google Scholar
33Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005; 23(5): 479-490.
10.1016/j.immuni.2005.09.015
CAS PubMed Web of Science® Google Scholar
34Hardman C, Ogg G. Interleukin-33, friend and foe in type-2 immune responses. Curr Opin Immunol. 2016; 42: 16-24.
10.1016/j.coi.2016.05.004
CAS PubMed Web of Science® Google Scholar
35Préfontaine D, Nadigel J, Chouiali F, et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J Allergy Clin Immunol. 2010; 125(3): 752-754.
10.1016/j.jaci.2009.12.935
CAS PubMed Web of Science® Google Scholar
36Préfontaine D, Lajoie-Kadoch S, Foley S, et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009; 183(8): 5094-5103.
10.4049/jimmunol.0802387
CAS PubMed Web of Science® Google Scholar
37Carriere V, Roussel L, Ortega N, et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci. 2007; 104(1): 282-287.
10.1073/pnas.0606854104
CAS PubMed Web of Science® Google Scholar
38Moussion C, Ortega N, Girard J-P. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PloS One. 2008; 3(10):e3331.
10.1371/journal.pone.0003331
PubMed Web of Science® Google Scholar
39Shimokawa C, Kanaya T, Hachisuka M, et al. Mast cells are crucial for induction of group 2 innate lymphoid cells and clearance of helminth infections. Immunity. 2017; 46(5): 863-874.e4.
10.1016/j.immuni.2017.04.017
CAS PubMed Web of Science® Google Scholar
40Savinko T, Matikainen S, Saarialho-Kere U, et al. IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J Invest Dermatol. 2012; 132(5): 1392-1400.
10.1038/jid.2011.446
CAS PubMed Web of Science® Google Scholar
41Saikumar Jayalatha AK, Hesse L, Ketelaar ME, Koppelman GH, Nawijn MC. The central role of IL-33/IL-1RL1 pathway in asthma: from pathogenesis to intervention. Pharmacol Ther. 2021; 225:107847. doi:10.1016/j.pharmthera.2021.107847
10.1016/j.pharmthera.2021.107847
CAS PubMed Web of Science® Google Scholar
42Drake LY, Kita H. IL-33: biological properties, functions, and roles in airway disease. Immunol Rev. 2017; 278(1): 173-184.
10.1111/imr.12552
CAS PubMed Web of Science® Google Scholar
43Lefrançais E, Duval A, Mirey E, et al. Central domain of IL-33 is cleaved by mast cell proteases for potent activation of group-2 innate lymphoid cells. Proc Natl Acad Sci. 2014; 111(43): 15502-15507.
10.1073/pnas.1410700111
CAS PubMed Web of Science® Google Scholar
44Smith D, Helgason H, Sulem P, et al. A rare IL33 loss-of-function mutation reduces blood eosinophil counts and protects from asthma. PLoS Genet. 2017; 13(3):e1006659. doi:10.1371/journal.pgen.1006659
10.1371/journal.pgen.1006659
PubMed Web of Science® Google Scholar
45Marwaha AK, Laxer R, Liang M, Muise AM, Eiwegger T. A chromosomal duplication encompassing Interleukin-33 causes a novel hyper IgE phenotype characterized by eosinophilic esophagitis and generalized autoimmunity. Gastroenterology. 2022; 163(2): 510-513.e3. doi:10.1053/j.gastro.2022.04.026
10.1053/j.gastro.2022.04.026
CAS PubMed Web of Science® Google Scholar
46Homsak E, Gruson D. Soluble ST2: a complex and diverse role in several diseases. Clin Chim Acta. 2020; 507: 75-87. doi:10.1016/j.cca.2020.04.011
10.1016/j.cca.2020.04.011
CAS PubMed Web of Science® Google Scholar
47Mitchell PD, Salter BM, Oliveria JP, et al. IL-33 and its receptor ST2 after inhaled allergen challenge in allergic asthmatics. Int Arch Allergy Immunol. 2018; 176(2): 133-142.
10.1159/000488015
CAS PubMed Web of Science® Google Scholar
48Hesse L, van Ieperen N, Habraken C, et al. Subcutaneous immunotherapy with purified Der p1 and 2 suppresses type 2 immunity in a murine asthma model. Allergy. 2018; 73(4): 862-874.
10.1111/all.13382
CAS PubMed Web of Science® Google Scholar
49Kaur D, Gomez E, Doe C, et al. IL-33 drives airway hyper-responsiveness through IL-13-mediated mast cell: airway smooth muscle crosstalk. Allergy. 2015; 70(5): 556-567. doi:10.1111/all.12593
10.1111/all.12593
CAS PubMed Web of Science® Google Scholar
50Lachowicz-Scroggins M, Woodruff P, Fahy J, Gordon E. Characterization of IL-33 and St2 expression in human asthma. Am J Respir Crit Care Med. 2013; 187:A1003.
Web of Science® Google Scholar
51Li Y, Wang W, Lv Z, et al. Elevated expression of IL-33 and TSLP in the airways of human asthmatics in vivo: a potential biomarker of severe refractory disease. J Immunol. 2018; 200(7): 2253-2262.
10.4049/jimmunol.1701455
CAS PubMed Web of Science® Google Scholar
52Fort MM, Cheung J, Yen D, et al. IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity. 2001; 15(6): 985-995.
10.1016/S1074-7613(01)00243-6
CAS PubMed Web of Science® Google Scholar
53Lee J, Ho W-H, Maruoka M, et al. IL-17 E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J Biol Chem. 2001; 276(2): 1660-1664.
10.1074/jbc.M008289200
CAS PubMed Web of Science® Google Scholar
54Wang Y-H, Angkasekwinai P, Lu N, et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC–activated Th2 memory cells. J Exp Med. 2007; 204(8): 1837-1847.
10.1084/jem.20070406
CAS PubMed Web of Science® Google Scholar
55Angkasekwinai P, Park H, Wang Y-H, et al. Interleukin 25 promotes the initiation of proallergic type 2 responses. J Exp Med. 2007; 204(7): 1509-1517.
10.1084/jem.20061675
CAS PubMed Web of Science® Google Scholar
56Kohanski MA, Workman AD, Patel NN, et al. Solitary chemosensory cells are a primary epithelial source of IL-25 in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2018; 142(2): 460-469. e7.
10.1016/j.jaci.2018.03.019
CAS PubMed Web of Science® Google Scholar
57Von Moltke J, Ji M, Liang H-E, Locksley RM. Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit. Nature. 2016; 529(7585): 221-225.
10.1038/nature16161
CAS PubMed Web of Science® Google Scholar
58Corrigan CJ, Wang W, Meng Q, et al. Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses. J Allergy Clin Immunol. 2011; 128(1): 116-124. doi:10.1016/j.jaci.2011.03.043
10.1016/j.jaci.2011.03.043
CAS PubMed Web of Science® Google Scholar
59Ikeda K, Nakajima H, Suzuki K, et al. Mast cells produce interleukin-25 upon FcεRI-mediated activation. Blood. 2003; 101(9): 3594-3596.
10.1182/blood-2002-09-2817
CAS PubMed Web of Science® Google Scholar
60Kang C-M, Jang A-S, Ahn M-H, et al. Interleukin-25 and interleukin-13 production by alveolar macrophages in response to particles. Am J Respir Cell Mol Biol. 2005; 33(3): 290-296.
10.1165/rcmb.2005-0003OC
CAS PubMed Web of Science® Google Scholar
61Rickel EA, Siegel LA, Yoon B-RP, et al. Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol. 2008; 181(6): 4299-4310.
10.4049/jimmunol.181.6.4299
CAS PubMed Web of Science® Google Scholar
62Chang SH, Dong C. Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal. 2011; 23(7): 1069-1075.
10.1016/j.cellsig.2010.11.022
CAS PubMed Web of Science® Google Scholar
63Tworek D, Smith SG, Salter BM, et al. IL-25 receptor expression on airway dendritic cells after allergen challenge in subjects with asthma. Am J Respir Crit Care Med. 2016; 193(9): 957-964. doi:10.1164/rccm.201509-1751OC
10.1164/rccm.201509-1751OC
CAS PubMed Web of Science® Google Scholar
64Li Z-G, Scott MJ, Brzoska T, et al. Lung epithelial cell-derived IL-25 negatively regulates LPS-induced exosome release from macrophages. Mil Med Res. 2018; 5(1): 1-11.
PubMed Web of Science® Google Scholar
65Cheung P, Wong C, Ip W, Lam C. IL-25 regulates the expression of adhesion molecules on eosinophils: mechanism of eosinophilia in allergic inflammation. Allergy. 2006; 61(7): 878-885.
10.1111/j.1398-9995.2006.01102.x
CAS PubMed Web of Science® Google Scholar
66Wang H, Mobini R, Fang Y, et al. Allergen challenge of peripheral blood mononuclear cells from patients with seasonal allergic rhinitis increases IL-17RB, which regulates basophil apoptosis and degranulation. Clin Exp Allergy. 2010; 40(8): 1194-1202.
10.1111/j.1365-2222.2010.03542.x
CAS PubMed Web of Science® Google Scholar
67Huang Y, Guo L, Qiu J, et al. IL-25-responsive, lineage-negative KLRG1 hi cells are multipotential ‘inflammatory’ type 2 innate lymphoid cells. Nat Immunol. 2015; 16(2): 161-169.
10.1038/ni.3078
CAS PubMed Web of Science® Google Scholar
68Petersen BC, Budelsky AL, Baptist AP, Schaller MA, Lukacs NW. Interleukin-25 induces type 2 cytokine production in a steroid-resistant interleukin-17RB+ myeloid population that exacerbates asthmatic pathology. Nat Med. 2012; 18(5): 751-758.
10.1038/nm.2735
CAS PubMed Web of Science® Google Scholar
69Terashima A, Watarai H, Inoue S, et al. A novel subset of mouse NKT cells bearing the IL-17 receptor B responds to IL-25 and contributes to airway hyperreactivity. J Exp Med. 2008; 205(12): 2727-2733.
10.1084/jem.20080698
CAS PubMed Web of Science® Google Scholar
70Kitajima M, Lee HC, Nakayama T, Ziegler SF. TSLP enhances the function of helper type 2 cells. Eur J Immunol. 2011; 41(7): 1862-1871.
10.1002/eji.201041195
CAS PubMed Web of Science® Google Scholar
71Cayrol C, Duval A, Schmitt P, et al. Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33. Nat Immunol. 2018; 19(4): 375-385. doi:10.1038/s41590-018-0067-5
10.1038/s41590-018-0067-5
CAS PubMed Web of Science® Google Scholar
72Ballantyne SJ, Barlow JL, Jolin HE, et al. Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol. 2007; 120(6): 1324-1331. doi:10.1016/j.jaci.2007.07.051
10.1016/j.jaci.2007.07.051
CAS PubMed Web of Science® Google Scholar
73Gauvreau GM, O'Byrne PM, Boulet LP, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med. 2014; 370(22): 2102-2110. doi:10.1056/NEJMoa1402895
10.1056/NEJMoa1402895
PubMed Web of Science® Google Scholar
74Gauvreau GM, Hohlfeld JM, Grant S, et al. Efficacy and safety of an inhaled anti-TSLP antibody fragment in adults with mild atopic asthma. Am J Respir Crit Care Med. 2020; 201(B93: Late breaking clinical trials in airway disease):A4207. doi:10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A4207
10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A4207
Google Scholar
75Gauvreau G, Hohlfeld J, Boulet L-P, et al. Late breaking abstract—efficacy of CSJ117 on allergen-induced asthmatic responses in mild atopic asthma patients. Eur Respir J. 2020; 56(suppl 64):3690. doi:10.1183/13993003.congress-2020.3690
10.1183/13993003.congress-2020.3690
Web of Science® Google Scholar
76Reddel HK, Busse WW, Pedersen S, et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet. 2017; 389(10065): 157-166. doi:10.1016/s0140-6736(16)31399-x
10.1016/S0140-6736(16)31399-X
PubMed Web of Science® Google Scholar
77Castillo JR, Peters SP, Busse WW. Asthma exacerbations: pathogenesis, prevention, and treatment. J Allergy Clin Immunol Pract. 2017; 5(4): 918-927. doi:10.1016/j.jaip.2017.05.001
10.1016/j.jaip.2017.05.001
PubMed Web of Science® Google Scholar
78Bai TR, Vonk JM, Postma DS, Boezen HM. Severe exacerbations predict excess lung function decline in asthma. Eur Respir J. 2007; 30(3): 452-456. doi:10.1183/09031936.00165106
10.1183/09031936.00165106
CAS PubMed Web of Science® Google Scholar
79O'Byrne PM, Pedersen S, Lamm CJ, Tan WC, Busse WW. Severe exacerbations and decline in lung function in asthma. Am J Respir Crit Care Med. 2009; 179(1): 19-24. doi:10.1164/rccm.200807-1126OC
10.1164/rccm.200807-1126OC
PubMed Web of Science® Google Scholar
80Hanania NA, Alpan O, Hamilos DL, et al. Omalizumab in severe allergic asthma inadequately controlled with standard therapy: a randomized trial. Ann Intern Med. 2011; 154(9): 573-582. doi:10.7326/0003-4819-154-9-201105030-00002
10.7326/0003-4819-154-9-201105030-00002
PubMed Web of Science® Google Scholar
81Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017; 377(10): 936-946. doi:10.1056/NEJMoa1704064
10.1056/NEJMoa1704064
CAS PubMed Web of Science® Google Scholar
82Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. 2021; 384(19): 1800-1809. doi:10.1056/NEJMoa2034975
10.1056/NEJMoa2034975
CAS PubMed Web of Science® Google Scholar
83FitzGerald JM, Bleecker ER, Nair P, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016; 388(10056): 2128-2141. doi:10.1016/S0140-6736(16)31322-8
10.1016/S0140-6736(16)31322-8
CAS PubMed Web of Science® Google Scholar
84Castro M, Wenzel SE, Bleecker ER, et al. Benralizumab, an anti-interleukin 5 receptor α monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014; 2(11): 879-890. doi:10.1016/S2213-2600(14)70201-2
10.1016/S2213-2600(14)70201-2
CAS PubMed Web of Science® Google Scholar
85Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018; 378(26): 2486-2496. doi:10.1056/NEJMoa1804092
10.1056/NEJMoa1804092
CAS PubMed Web of Science® Google Scholar
86Corren J, Lemanske RF, Hanania NA, et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011; 365(12): 1088-1098. doi:10.1056/NEJMoa1106469
10.1056/NEJMoa1106469
CAS PubMed Web of Science® Google Scholar
87Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet. 2016; 388(10039): 31-44. doi:10.1016/S0140-6736(16)30307-5
10.1016/S0140-6736(16)30307-5
CAS PubMed Web of Science® Google Scholar
88Pavord ID, Korn S, Howarth P, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012; 380(9842): 651-659. doi:10.1016/s0140-6736(12)60988-x
10.1016/S0140-6736(12)60988-X
CAS PubMed Web of Science® Google Scholar
89Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015; 3(5): 355-366. doi:10.1016/S2213-2600(15)00042-9
10.1016/S2213-2600(15)00042-9
CAS PubMed Web of Science® Google Scholar
90FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med. 2018; 6(1): 51-64. doi:10.1016/S2213-2600(17)30344-2
10.1016/S2213-2600(17)30344-2
CAS PubMed Web of Science® Google Scholar
91Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013; 368(26): 2455-2466. doi:10.1056/NEJMoa1304048
10.1056/NEJMoa1304048
CAS PubMed Web of Science® Google Scholar
92Watanabe N, Hanabuchi S, Soumelis V, et al. Human thymic stromal lymphopoietin promotes dendritic cell–mediated CD4+ T cell homeostatic expansion. Nat Immunol. 2004; 5(4): 426-434.
10.1038/ni1048
CAS PubMed Web of Science® Google Scholar
93Arima K, Watanabe N, Hanabuchi S, Chang M, Sun S-C, Liu Y-J. Distinct signal codes generate dendritic cell functional plasticity. Sci Signal. 2010; 3(105):ra4.
10.1126/scisignal.2000567
PubMed Web of Science® Google Scholar
94Ito T, Wang Y-H, Duramad O, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005; 202(9): 1213-1223.
10.1084/jem.20051135
CAS PubMed Web of Science® Google Scholar
95Lee JY, Lim YM, Park MJ, et al. Murine thymic stromal lymphopoietin promotes the differentiation of regulatory T cells from thymic CD4+ CD8− CD25− naïve cells in a dendritic cell-independent manner. Immunol Cell Biol. 2008; 86(2): 206-213.
10.1038/sj.icb.7100127
CAS PubMed Web of Science® Google Scholar
96Mazzucchelli R, Hixon JA, Spolski R, et al. Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP. Blood. 2008; 112(8): 3283-3292.
10.1182/blood-2008-02-137414
CAS PubMed Web of Science® Google Scholar
97Wang Y-H, Ito T, Wang Y-H, et al. Maintenance and polarization of human TH2 central memory T cells by thymic stromal lymphopoietin-activated dendritic cells. Immunity. 2006; 24(6): 827-838.
10.1016/j.immuni.2006.03.019
CAS PubMed Web of Science® Google Scholar
98Akamatsu T, Watanabe N, Kido M, et al. Human TSLP directly enhances expansion of CD8+ T cells. Clin Exp Immunol. 2008; 154(1): 98-106.
10.1111/j.1365-2249.2008.03731.x
CAS PubMed Web of Science® Google Scholar
99Rochman Y, Dienger-Stambaugh K, Richgels PK, et al. TSLP signaling in CD4+ T cells programs a pathogenic T helper 2 cell state. Sci Signal. 2018; 11(521):eaam8858.
10.1126/scisignal.aam8858
PubMed Web of Science® Google Scholar
100Omori M, Ziegler S. Induction of IL-4 expression in CD4+ T cells by thymic stromal lymphopoietin. J Immunol. 2007; 178(3): 1396-1404.
10.4049/jimmunol.178.3.1396
CAS PubMed Web of Science® Google Scholar
101Friend SL, Hosier S, Nelson A, Foxworthe D, Williams D, Farr A. A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells. Exp Hematol. 1994; 22(3): 321-328.
CAS PubMed Web of Science® Google Scholar
102Levin SD, Koelling RM, Friend SL, et al. Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+ B cells in vitro and signals via a novel mechanism. J Immunol. 1999; 162(2): 677-683.
10.4049/jimmunol.162.2.677
CAS PubMed Web of Science® Google Scholar
103Scheeren FA, van Lent AU, Nagasawa M, et al. Thymic stromal lymphopoietin induces early human B-cell proliferation and differentiation. Eur J Immunol. 2010; 40(4): 955-965. doi:10.1002/eji.200939419
10.1002/eji.200939419
CAS PubMed Web of Science® Google Scholar
104Nguyen KD, Vanichsarn C, Nadeau KC. TSLP directly impairs pulmonary Treg function: association with aberrant tolerogenic immunity in asthmatic airway. Allergy Asthma Clin Immunol. 2010; 6(1): 1-11.
10.1186/1710-1492-6-4
PubMed Google Scholar
105Smith SG, Chen R, Kjarsgaard M, et al. Increased numbers of activated group 2 innate lymphoid cells in the airways of patients with severe asthma and persistent airway eosinophilia. J Allergy Clin Immunol. 2016; 137(1): 75-86.e8. doi:10.1016/j.jaci.2015.05.037
10.1016/j.jaci.2015.05.037
CAS PubMed Web of Science® Google Scholar
106Machida K, Aw M, Salter BMA, et al. The role of the TL1A/DR3 axis in the activation of group 2 innate lymphoid cells in subjects with eosinophilic asthma. Am J Respir Crit Care Med. 2020; 202(8): 1105-1114. doi:10.1164/rccm.201909-1722OC
10.1164/rccm.201909-1722OC
CAS PubMed Web of Science® Google Scholar
107Toki S, Goleniewska K, Zhang J, et al. TSLP and IL-33 reciprocally promote each other's lung protein expression and ILC2 receptor expression to enhance innate type-2 airway inflammation. Allergy. 2020; 75(7): 1606-1617. doi:10.1111/all.14196
10.1111/all.14196
CAS PubMed Web of Science® Google Scholar
108Camelo A, Rosignoli G, Ohne Y, et al. IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells. Blood Adv. 2017; 1(10): 577-589.
10.1182/bloodadvances.2016002352
CAS PubMed Web of Science® Google Scholar
109Menzies-Gow A, Corren J, Bourdin A, et al. Efficacy and safety of Tezepelumab in adults and adolescents with severe, uncontrolled asthma: results from the phase 3 NAVIGATOR study. J Allergy Clin Immunol. 2021; 147(2):AB249. doi:10.1016/j.jaci.2020.12.050
10.1016/j.jaci.2020.12.050
Web of Science® Google Scholar
110Corren J, Karpefors M, Hellqvist Å, Parnes JR, Colice G. Tezepelumab reduces exacerbations across all seasons in patients with severe, uncontrolled asthma: a post hoc analysis of the PATHWAY phase 2b study. J Asthma Allergy. 2021; 14: 1-11. doi:10.2147/jaa.s286036
10.2147/JAA.S286036
CAS PubMed Web of Science® Google Scholar
111Corren J, Ambrose CS, Sałapa K, et al. Efficacy of Tezepelumab in patients with severe, uncontrolled asthma and perennial allergy. J Allergy Clin Immunol Pract. 2021; 9(12): 4334-4342.e6. doi:10.1016/j.jaip.2021.07.045
10.1016/j.jaip.2021.07.045
CAS PubMed Web of Science® Google Scholar
112Emson C, Corren J, Sałapa K, Hellqvist Å, Parnes JR, Colice G. Efficacy of Tezepelumab in patients with severe, uncontrolled asthma with and without nasal polyposis: a post hoc analysis of the phase 2b PATHWAY study. J Asthma Allergy. 2021; 14: 91-99. doi:10.2147/jaa.s288260
10.2147/JAA.S288260
CAS PubMed Web of Science® Google Scholar
113Eiwegger T, Akdis CA. IL-33 links tissue cells, dendritic cells and Th2 cell development in a mouse model of asthma. Eur J Immunol. 2011; 41(6): 1535-1538.
10.1002/eji.201141668
CAS PubMed Web of Science® Google Scholar
114Rank MA, Kobayashi T, Kozaki H, Bartemes KR, Squillace DL, Kita H. IL-33–activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol. 2009; 123(5): 1047-1054.
10.1016/j.jaci.2009.02.026
CAS PubMed Web of Science® Google Scholar
115Bouffi C, Rochman M, Zust CB, et al. IL-33 markedly activates murine eosinophils by an NF-κB–dependent mechanism differentially dependent upon an IL-4–driven autoinflammatory loop. J Immunol. 2013; 191(8): 4317-4325.
10.4049/jimmunol.1301465
CAS PubMed Web of Science® Google Scholar
116Jung M-Y, Smrž D, Desai A, et al. IL-33 induces a hyporesponsive phenotype in human and mouse mast cells. J Immunol. 2013; 190(2): 531-538.
10.4049/jimmunol.1201576
CAS PubMed Web of Science® Google Scholar
117Kurowska-Stolarska M, Stolarski B, Kewin P, et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J Immunol. 2009; 183(10): 6469-6477.
10.4049/jimmunol.0901575
CAS PubMed Web of Science® Google Scholar
118Joshi AD, Oak SR, Hartigan AJ, et al. Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages. BMC Immunol. 2010; 11(1): 1-10.
10.1186/1471-2172-11-52
PubMed Web of Science® Google Scholar
119Liu T, Barrett NA, Kanaoka Y, et al. Type 2 Cysteinyl leukotriene receptors drive IL-33–dependent type 2 immunopathology and aspirin sensitivity. J Immunol. 2018; 200(3): 915-927.
10.4049/jimmunol.1700603
CAS PubMed Web of Science® Google Scholar
120Halim TY, Rana BM, Walker JA, et al. Tissue-restricted adaptive type 2 immunity is orchestrated by expression of the costimulatory molecule OX40L on group 2 innate lymphoid cells. Immunity. 2018; 48(6): 1195-1207. e6.
10.1016/j.immuni.2018.05.003
CAS PubMed Web of Science® Google Scholar
121Chen R, Smith SG, Salter B, et al. Allergen-induced increases in sputum levels of group 2 innate lymphoid cells in subjects with asthma. Am J Respir Crit Care Med. 2017; 196(6): 700-712. doi:10.1164/rccm.201612-2427OC
10.1164/rccm.201612-2427OC
CAS PubMed Web of Science® Google Scholar
122Vocca L, Di Sano C, Uasuf CG, et al. IL-33/ST2 axis controls Th2/IL-31 and Th17 immune response in allergic airway diseases. Immunobiology. 2015; 220(8): 954-963.
10.1016/j.imbio.2015.02.005
CAS PubMed Web of Science® Google Scholar
123Funakoshi-Tago M, Tago K, Sato Y, Tominaga S-i, Kasahara T. JAK2 is an important signal transducer in IL-33-induced NF-κB activation. Cell Signal. 2011; 23(2): 363-370.
10.1016/j.cellsig.2010.10.006
CAS PubMed Web of Science® Google Scholar
124Endo Y, Hirahara K, Iinuma T, et al. The interleukin-33-p38 kinase axis confers memory T helper 2 cell pathogenicity in the airway. Immunity. 2015; 42(2): 294-308.
10.1016/j.immuni.2015.01.016
CAS PubMed Web of Science® Google Scholar
125Blom L, Poulsen BC, Jensen BM, Hansen A, Poulsen LK. IL-33 induces IL-9 production in human CD4+ T cells and basophils. PloS One. 2011; 6(7):e21695.
10.1371/journal.pone.0021695
CAS PubMed Web of Science® Google Scholar
126Ravanetti L, Dijkhuis A, Dekker T, et al. IL-33 drives influenza-induced asthma exacerbations by halting innate and adaptive antiviral immunity. J Allergy Clin Immunol. 2019; 143(4): 1355-1370.e16. doi:10.1016/j.jaci.2018.08.051
10.1016/j.jaci.2018.08.051
CAS PubMed Web of Science® Google Scholar
127Jackson DJ, Makrinioti H, Rana BM, et al. IL-33-dependent type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo. Am J Respir Crit Care Med. 2014; 190(12): 1373-1382. doi:10.1164/rccm.201406-1039OC
10.1164/rccm.201406-1039OC
CAS PubMed Web of Science® Google Scholar
128Wechsler ME, Ruddy MK, Pavord ID, et al. Efficacy and safety of Itepekimab in patients with moderate-to-severe asthma. N Engl J Med. 2021; 385(18): 1656-1668. doi:10.1056/NEJMoa2024257
10.1056/NEJMoa2024257
CAS PubMed Web of Science® Google Scholar
129Kelsen SG, Agache IO, Soong W, et al. Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: a randomized clinical trial. J Allergy Clin Immunol. 2021; 148(3): 790-798. doi:10.1016/j.jaci.2021.03.044
10.1016/j.jaci.2021.03.044
CAS PubMed Web of Science® Google Scholar
130Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM. Asthma. From bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med. 2000; 161(5): 1720-1745. doi:10.1164/ajrccm.161.5.9903102
10.1164/ajrccm.161.5.9903102
CAS PubMed Web of Science® Google Scholar
131Cao L, Liu F, Liu Y, et al. TSLP promotes asthmatic airway remodeling via p38-STAT3 signaling pathway in human lung fibroblast. Exp Lung Res. 2018; 44(6): 288-301. doi:10.1080/01902148.2018.1536175
10.1080/01902148.2018.1536175
PubMed Web of Science® Google Scholar
132Guo Z, Wu J, Zhao J, et al. IL-33 promotes airway remodeling and is a marker of asthma disease severity. J Asthma. 2014; 51(8): 863-869. doi:10.3109/02770903.2014.921196
10.3109/02770903.2014.921196
CAS PubMed Web of Science® Google Scholar
133Shan L, Redhu NS, Saleh A, Halayko AJ, Chakir J, Gounni AS. Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways. J Immunol. 2010; 184(12): 7134-7143.
10.4049/jimmunol.0902515
CAS PubMed Web of Science® Google Scholar
134Ni G, Chen Y, Wu F, Zhu P, Song L. NOD2 promotes cell proliferation and inflammatory response by mediating expression of TSLP in human airway smooth muscle cells. Cell Immunol. 2017; 312: 35-41.
10.1016/j.cellimm.2016.11.007
CAS PubMed Web of Science® Google Scholar
135Lajoie-Kadoch S, Joubert P, Létuvé S, et al. TNF-α and IFN-γ inversely modulate expression of the IL-17 E receptor in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2006; 290(6): L1238-L1246.
10.1152/ajplung.00301.2005
CAS PubMed Web of Science® Google Scholar
136Cheng D, Xue Z, Yi L, et al. Epithelial interleukin-25 is a key mediator in Th2-high, corticosteroid-responsive asthma. Am J Respir Crit Care Med. 2014; 190(6): 639-648. doi:10.1164/rccm.201403-0505OC
10.1164/rccm.201403-0505OC
CAS PubMed Web of Science® Google Scholar
137Jessup HK, Allakhverdi Z, Comeau MR, Park-Yoon B-R, Ziegler SF, Delespesse G. Thymic stromal lymphopoietin (TSLP) is a potent activator of human mast cells (38.4). J Immunol. 2007; 178(1_Suppl): S23.
10.4049/jimmunol.178.Supp.38.4
Google Scholar
138Salter BM, Oliveria JP, Nusca G, et al. Thymic stromal lymphopoietin activation of basophils in patients with allergic asthma is IL-3 dependent. J Allergy Clin Immunol. 2015; 136(6): 1636-1644. doi:10.1016/j.jaci.2015.03.039
10.1016/j.jaci.2015.03.039
CAS PubMed Web of Science® Google Scholar
139Hui CC, Rusta-Sallehy S, Asher I, Heroux D, Denburg JA. The effects of thymic stromal lymphopoietin and IL-3 on human eosinophil-basophil lineage commitment: relevance to atopic sensitization. Immun Inflamm Dis. 2014; 2(1): 44-55. doi:10.1002/iid3.20
10.1002/iid3.20
CAS PubMed Google Scholar
140Smithgall MD, Comeau MR, Park Yoon B-R, Kaufman D, Armitage R, Smith DE. IL-33 amplifies both Th1-and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int Immunol. 2008; 20(8): 1019-1030.
10.1093/intimm/dxn060
CAS PubMed Web of Science® Google Scholar
141Rivellese F, Suurmond J, de Paulis A, Marone G, Huizinga TW, Toes RE. IgE and IL-33− mediated triggering of human basophils inhibits TLR4− induced monocyte activation. Eur J Immunol. 2014; 44(10): 3045-3055.
10.1002/eji.201444731
CAS PubMed Web of Science® Google Scholar
142Suzukawa M, Iikura M, Koketsu R, et al. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J Immunol. 2008; 181(9): 5981-5989.
10.4049/jimmunol.181.9.5981
CAS PubMed Web of Science® Google Scholar
143Pecaric-Petkovic T, Didichenko SA, Kaempfer S, Spiegl N, Dahinden CA. Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood. 2009; 113(7): 1526-1534.
10.1182/blood-2008-05-157818
CAS PubMed Web of Science® Google Scholar
144Salter BM, Oliveria JP, Nusca G, et al. IL-25 and IL-33 induce type 2 inflammation in basophils from subjects with allergic asthma. Respir Res. 2016; 17:5. doi:10.1186/s12931-016-0321-z
10.1186/s12931-016-0321-z
PubMed Web of Science® Google Scholar
145Ro M, Lee AJ, Kim JH. 5−/12-lipoxygenase-linked cascade contributes to the IL-33-induced synthesis of IL-13 in mast cells, thus promoting asthma development. Allergy. 2018; 73(2): 350-360.
10.1111/all.13294
CAS PubMed Web of Science® Google Scholar
146Juniper EF, Frith PA, Dunnett C, Cockcroft DW, Hargreave FE. Reproducibility and comparison of responses to inhaled histamine and methacholine. Thorax. 1978; 33(6): 705-710.
10.1136/thx.33.6.705
CAS PubMed Web of Science® Google Scholar
147Anderson SD, Brannan J, Spring J, et al. A new method for bronchial-provocation testing in asthmatic subjects using a dry powder of mannitol. Am J Respir Crit Care Med. 1997; 156(3 Pt 1): 758-765. doi:10.1164/ajrccm.156.3.9701113
10.1164/ajrccm.156.3.9701113
CAS PubMed Web of Science® Google Scholar
148Diver S, Khalfaoui L, Emson C, et al. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir Med. 2021; 9(11): 1299-1312. doi:10.1016/s2213-2600(21)00226-5
10.1016/S2213-2600(21)00226-5
CAS PubMed Web of Science® Google Scholar
149Sverrild A, Hansen S, Hvidtfeldt M, et al. The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM). Eur Respir J. 2021; 59(1): 2101296. doi:10.1183/13993003.01296-2021
10.1183/13993003.01296-2021
PubMed Web of Science® Google Scholar
150Allakhverdi Z, Comeau MR, Smith DE, et al. CD34+ hemopoietic progenitor cells are potent effectors of allergic inflammation. J Allergy Clin Immunol. 2009; 123(2): 472-478. doi:10.1016/j.jaci.2008.10.022
10.1016/j.jaci.2008.10.022
CAS PubMed Web of Science® Google Scholar
151Busse WW, Holgate S, Kerwin E, et al. Randomized, double-blind, placebo-controlled study of brodalumab, a human anti-IL-17 receptor monoclonal antibody, in moderate to severe asthma. Am J Respir Crit Care Med. 2013; 188(11): 1294-1302. doi:10.1164/rccm.201212-2318OC
10.1164/rccm.201212-2318OC
CAS PubMed Web of Science® Google Scholar
152Salter BMA, Smith SG, Mukherjee M, et al. Human bronchial epithelial cell-derived factors from severe asthmatic subjects stimulate eosinophil differentiation. Am J Respir Cell Mol Biol. 2017; 58: 99-106. doi:10.1165/rcmb.2016-0262OC
10.1165/rcmb.2016-0262OC
Web of Science® Google Scholar
153Hui CC, Asher I, Heroux D, Allakhverdi Z, Delespesse G, Denburg JA. Effects of thymic stromal lymphopoietin on cord blood progenitor cell differentiation and hemopoietic cytokine receptors expression. Allergy, Asthma Clin Immunol. 2011; 7(Suppl 2):A24.
Google Scholar
154Wong CK, Hu S, Cheung PF, Lam CW. Thymic stromal lymphopoietin induces chemotactic and prosurvival effects in eosinophils: implications in allergic inflammation. Am J Respir Cell Mol Biol. 2010; 43(3): 305-315.
10.1165/rcmb.2009-0168OC
CAS PubMed Web of Science® Google Scholar
155Suzukawa M, Koketsu R, Iikura M, et al. Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab Invest. 2008; 88(11): 1245-1253.
10.1038/labinvest.2008.82
CAS PubMed Web of Science® Google Scholar
156Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol. 2008; 121(6): 1484-1490.
10.1016/j.jaci.2008.04.005
CAS PubMed Web of Science® Google Scholar
157Smith SG, Gugilla A, Mukherjee M, et al. Thymic stromal lymphopoietin and IL-33 modulate migration of hematopoietic progenitor cells in patients with allergic asthma. J Allergy Clin Immunol. 2015; 135(6): 1594-1602. doi:10.1016/j.jaci.2014.12.1918
10.1016/j.jaci.2014.12.1918
CAS PubMed Web of Science® Google Scholar
158Wong CK, Cheung PF, Ip WK, Lam CW. Interleukin-25–induced chemokines and interleukin-6 release from eosinophils is mediated by p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-κB. Am J Respir Cell Mol Biol. 2005; 33(2): 186-194.
10.1165/rcmb.2005-0034OC
CAS PubMed Web of Science® Google Scholar
159Tang W, Smith SG, Du W, et al. Interleukin-25 and eosinophils progenitor cell mobilization in allergic asthma. Clin Transl Allergy. 2018; 8:5. doi:10.1186/s13601-018-0190-2
10.1186/s13601-018-0190-2
PubMed Web of Science® Google Scholar
160Whetstone CE, Ranjbar M, Omer H, Cusack RP, Gauvreau GM. The role of airway epithelial cell alarmins in asthma. Cells. 2022; 11(7): 1105. doi:10.3390/cells11071105
10.3390/cells11071105
CAS PubMed Web of Science® Google Scholar

Citing Literature

Volume78, Issue2

February 2023

Pages 402-417

Sounding the alarmins—The role of alarmin cytokines in asthma

Abstract

1 INTRODUCTION

2 ALARMIN EXPRESSION AND ASTHMA

3 CLINICAL TRIALS OF ANTI-ALARMINS IN ASTHMA

4 ASTHMA EXACERBATION

4.1 Mechanism of TSLP in exacerbations

4.2 Anti-TSLP and exacerbation outcomes in clinical trials

4.3 Mechanism of IL-33 in exacerbations

4.4 IL-33 pathway and exacerbation outcomes in clinical trials

5 LUNG FUNCTION

5.1 Mechanisms of alarmins in lung function and AHR

5.2 Anti-TSLP and measures of airway hyperresponsiveness in clinical trials

5.3 Anti-TSLP and measures of lung function in clinical trials

5.4 IL-33 pathway blockade and measures of lung function in clinical trials

5.5 IL-25 blockade and measures of lung function in clinical trials

6 ALARMINS AND INFLAMMATORY BIOMARKERS

7 CONCLUSION

ACKNOWLEDGMENTS

CONFLICT OF INTEREST

REFERENCES

Citing Literature

Figures

References

Information

About Wiley Online Library

Help & Support

Opportunities

Connect with Wiley

Sounding the alarmins—The role of alarmin cytokines in asthma

Abstract

1 INTRODUCTION

2 ALARMIN EXPRESSION AND ASTHMA

3 CLINICAL TRIALS OF ANTI-ALARMINS IN ASTHMA

4 ASTHMA EXACERBATION

4.1 Mechanism of TSLP in exacerbations

4.2 Anti-TSLP and exacerbation outcomes in clinical trials

4.3 Mechanism of IL-33 in exacerbations

4.4 IL-33 pathway and exacerbation outcomes in clinical trials

5 LUNG FUNCTION

5.1 Mechanisms of alarmins in lung function and AHR

5.2 Anti-TSLP and measures of airway hyperresponsiveness in clinical trials

5.3 Anti-TSLP and measures of lung function in clinical trials

5.4 IL-33 pathway blockade and measures of lung function in clinical trials

5.5 IL-25 blockade and measures of lung function in clinical trials

6 ALARMINS AND INFLAMMATORY BIOMARKERS

7 CONCLUSION

ACKNOWLEDGMENTS

CONFLICT OF INTEREST

REFERENCES

Citing Literature

Figures

References

Related

Information