1. Background

Smells are important sensation in daily life. They not only bring joy during eating, but also cause discomfort when smelling foul odors. The smell of burning and food spoilage can help avoid dangerous situations, such as fire and food poisoning. Therefore, when olfactory disorders occur, they not only reduce the quality of life of patients, but may also pose a threat to their lives [1, 2]. Olfactory dysfunction (OD) refers to the abnormal perception of odors caused by qualitative and/or functional lesions in various links of the olfactory pathway during odor perception, transmission, and integration of information analysis. OD includes both quantitative and qualitative olfactory impairment. The former includes decreased sense of smell, loss of smell, and olfactory hypersensitivity, whereas the latter includes olfactory inversion and hallucinations [3]. In the traditional classification, OD is divided into two categories: conductive and neuropathic. Conductive OD is typically caused by diseases or injuries to the nasal cavity, throat, and other areas, such as sinusitis and nasal polyps, these diseases affect the transmission of odor molecules to olfactory cells, whereas neuropathic OD is mostly caused by central nervous system lesions, such as head trauma and Parkinson’s disease (PD). These lesions affect processing and recognition of olfactory signals [4–6]. In recent years, it has been suggested that OD should no longer be classified as conductive or neuropathic because chronic sinusitis with OD after infection often involves both components. Therefore, the latest classification shows that similar to age-related functional impairments, OD should be classified as congenital and acquired [7–9]. The incidence of OD in the population reaches up to 40%; however, current attention to OD is still insufficient, which is mainly attributed to the lack of objective, effective, and convenient methods for OD identification. At present, the olfactory psychophysical tests commonly used in clinical practice, including subjective visual analog scale (VAS) evaluation and expensive and complex imaging and neurophysiological examinations, have poor patient cooperation and low completion rates. The recognition rate of OD detected by the above methods is only 27% [10]. Therefore, exploring simpler and more efficient methods is currently an important direction in OD research with high expectations for hematological markers. Interleukin-6 (IL-6) has been used as an inflammatory marker in the clinical evaluation of patients with inflammation, infections, or immune disorders. Several studies have reported that IL-6 expression is associated with OD in various diseases (Table 1 [11–15]). However, the role of IL-6 in the occurrence and development of OD remains unclear, which affects its clinical application. This article reviews the characteristics and possible mechanisms of IL-6 changes in various diseases associated with OD to provide evidence for the clinical application of IL-6 as a biomarker of OD and to promote in-depth exploration of its mechanism of action in the occurrence and development of OD.

2. Introduction to IL-6

IL-6 is a typical member of the IL-6 cytokine family, which consists of 10 members, including IL-6, interleukin-11 (IL-11), interleukin-27 (IL-27), oncostatin M (OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1). Otropin-like cytokine factor 1 (CLCF1), interleukin-35 (IL-35), and interleukin-39 (IL-39) have also been identified [16]. IL-6 is a single-chain glycoprotein with a relative molecular mass of 21–30 kD containing 212 amino acid residues, and its gene is localized on chromosome 7. IL-6 is an inflammatory factor with two types of receptors: the membrane receptor mIL-6R, which is expressed on the cell membrane surface, and the soluble receptor sIL-6R, which is present in the circulatory system. They cannot transduce intracellular signals on their own and require assistance from the transmembrane protein gp130 (CD130) [17–19]. IL-6 has both pro-inflammatory and anti-inflammatory properties and acts via different signaling pathways. Within the classic signaling pathway, IL-6 binds to mIL-6R and forms a high-affinity IL-6/mIL-6R/gp130 complex with gp130. Soluble IL-6 receptor (sIL-6R) can be generated by the proteases ADAM17 (a disintegrin and metalloproteinase 17), and then IL-6 binds to sIL-6R in circulation and further forms the IL-6/sIL-6R/gp130 complex with gp130 [20, 21]. Both IL-6/mIL-6R/gp130 and IL-6/sIL-6R/gp130 complexes can activate the JAK pathway, leading to tyrosine residue phosphorylation on gp130. However, the IL-6/mIL-6R/gp130 complex recruits and phosphorylates Signal Transducers and Activators of Transcription 3 (STAT3), which then forms dimers, moves to the nucleus, and promotes suppressor of cytokine signaling 3(SOCS3) transcription. SOCS3 directly inhibits JAK kinases, thereby preventing further phosphorylation of STAT proteins [22]. In addition to activating the JAK/STAT pathway, phosphatase SHP-2 is recruited to tyrosine-phosphorylated gp130 and further phosphorylated by JAK1, mediating the Ras-Raf-MAPK signaling involved in cell proliferation and differentiation. This process regulates ERK1/2, promoting transcription factors for anti-inflammatory cytokine expression, while SHP2 and the protein inhibitor of activated STAT (PIAS) can help alleviate inflammation and promote tissue repair [23, 24]. The PI3K/Akt (phosphatidylinositide-3-kinase) signaling pathway is also activated, promoting cell survival and proliferation. This helps restore tissues during inflammation resolution [25, 26]. However, following the binding and signal transduction of the IL-6/sIL-6R/gp130 complex, the phosphorylated STAT3 dimer translocates to the nucleus, promoting the transcription of pro-inflammatory cytokines like IL-1β and tumor necrosis factor-α (TNF-α), thereby intensifying the inflammatory response [27]. At the same time, activation of MAPK pathway leads to the production of pro-inflammatory cytokines and chemokines [28]. The IL-6/sIL-6R/gp130 complex also activates the NF-κB pathway. Activated NF-κB then translocates to the nucleus and forms dimers, promoting the transcription of pro-inflammatory genes [29–31]. Additionally, Sylvia Hein et al. [32] proposed in 2017 that IL-6 cluster signaling is the third mode of IL-6 signaling. Their research indicate that DCs are able to trans-present IL-6 through a complex containing DC-expressed IL-6Rα bound to IL-6 that can interact with gp130 expressed on T cells, leading to the targeted activation of STAT3 in antigen specific T cells, mediating pathogenic T cell differentiation. Three IL-6 signaling pathways and downstream signal transduction in the cells can be seen in Figure 1.

IL-6 is a multifunctional cytokine that is produced by macrophages, dendritic cells, neutrophils, B cells, and some CD4+T cells. It is secreted by endothelial cells, fibroblasts, and epithelial cells [33]. IL-6 regulates the growth and differentiation of various tissues and promotes the activation of acute-phase proteins, including C-reactive protein (CRP) and fibrinogen, thereby inducing systemic inflammation [34, 35]. At the same time, many key factors in autoimmune diseases and cancer also play a role mainly through IL-6 signaling transduction factors and the STAT3 pathway [36]. Previous studies have shown that IL-6 is overexpressed in cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, kidney disease, hepatitis, schizophrenia, preeclampsia, tumors, periodontal disease, and other diseases [37–42]. After central nervous system damage, such as traumatic brain injury, the expression of IL-6 in the cerebrospinal fluid increases, which can trigger the secretion of nerve growth factors in astrocytes [43]. Many studies have shown that IL-6 is closely related to the occurrence and development of OD in various diseases; however, its specific mechanism of action remains unclear. IL-6, as an endogenous substance, has been shown to regulate the activity of neurons and glial cells, and can be regulated by TNF-α or directly inhibit olfactory function by activating the apoptotic pathway through neurotransmitters [44]. The expression level of IL-6 in the olfactory system is closely related to olfactory function. In patients with OD, the expression levels of IL-6 are often increased, indicating that IL-6 may be involved in the pathological and physiological processes of OD. Neuroimmune inflammatory responses are key factors in the onset and progression of OD. As one of the central mediators of immune-inflammatory responses, IL-6 is closely associated with the pathogenesis of OD. A study by Ullah MN et al. highlighted that the olfactory epithelium not only serves a sensory function but also plays a role in immune defense. Chronic inflammation of the nasal mucosa is strongly linked to OD, and elevated IL-6 levels can impair the barrier function of nasal epithelial cells, triggering neuroinflammation and leading to olfactory impairment. Furthermore, through a positive feedback mechanism, increased IL-6 levels exacerbate OD, a finding consistent with the research of Song et al. [45, 46]. Additionally, a study by Leon M et al. demonstrated that elevated IL-6 can further promote the release of other inflammatory mediators, such as IL-1β and TNF-α, through a positive feedback loop, contributing to the deterioration of olfactory function. The release of these inflammatory factors, in turn, enhances IL-6 production, further exacerbating the inflammatory response [47]. Therefore, an in-depth study of the relationship between IL-6 and OD not only helps to reveal the pathogenesis of OD but may also provide new ideas and methods for the treatment of OD.

3. IL-6 and Disease-Related OD

4. IL-6 Regulation in the Olfactory Function

5. Summary and Prospect

Although there has been increasing clinical attention to OD, prevention and treatment of OD remain challenging. At present, the treatment plans for OD mainly include the following: (i) treatment of the etiology of the disease if there is a clear primary cause; (ii) pharmacological treatment with glucocorticoids, vitamin A, ginkgo biloba, and other agents, to improve the local inflammation or nutritional support of the nerves [114–116]; (iii) surgical treatment of deviated septum and nasal polyps and similar interventions to improve the structure of the nasal cavity and ensure that the olfactory molecules can effectively contact the olfactory zone effector cells or neurons; (iv) olfactory training treatment; and (v) other treatments. In addition to the medicinal and surgical treatments mentioned above, some physical therapies, such as olfactory training, are also widely used in the treatment of OD. Olfactory training is a cognitive–behavioral intervention to enhance olfactory ability through repeated sniffing and inhalation of various olfactory agents and is supported by level 1A evidence. Since Hummel et al. first pointed out in 2009 that patients with OD can enhance their olfactory function through olfactory training, many studies have confirmed that olfactory training can be useful for the treatment of OD caused by viral infection, trauma, and neurological injury, helping to restore the function of the olfactory nerve, improve the olfactory recognition ability of patients with OD, and improve their quality of life [117–119]. However, these methods have limitations.

There are currently various methods for olfactory detection, such as the University of Pennsylvania Smell Identification Test (UPSIT), Sniffin ’Sticks Test, Odor Identification Task (OIT), and so on. Among them, UPSIT is currently the most widely used for olfactory recognition and detection. It consists of 40 items, each corresponding to a common odor [120, 121]. Each correct recognition earns 1 point, with a maximum score of 40 points. A score below 30 indicates that the patient has olfactory impairment. UPSIT is widely used in research, clinical trials, and medical diagnosis due to its easily recognizable odor and high sensitivity. It cannot be denied that UPSIT has its detection advantages, but there are also shortcomings. For example, in poverty-stricken or medically underdeveloped areas, there are still certain difficulties in operating UPSIT, and this test also requires professional personnel to guide the operation, which increases manpower to a certain extent. The detection of IL-6 only requires the extraction of 3–5 ml of blood sample, which can be completed in the laboratory of a regular hospital without the need for separate professional personnel. Therefore, theoretically, the detection completion rate of IL-6 is higher than that of UPSIT. At present, IL-6 is associated with OD in many diseases. When patients’ economic conditions permit, psychophysical testing combined with IL-6 can be used for detection, we can not only measure changes in olfactory ability, but also understand the degree of OD and potential recovery ability through monitoring IL-6 levels. Therefore, IL-6 is not only a diagnostic tool, but also provides clues about the mechanisms of OD. IL-6 can serve as both a diagnostic marker and a therapeutic marker, and is a simple and reproducible biomarker with high clinical potential, especially in early screening, diagnosis, and monitoring of disease progression.

With the gradual increase in studies on the correlation between IL-6 and OD, it has been observed that IL-6 is highly expressed, has a positive correlation with OD in most OD-related diseases, and plays an important regulatory role in the maintenance of the structure and function of the olfactory system. Based on the above, IL-6 is not only a marker of OD, but also may be a potential target in OD diagnosis. Some therapeutic approaches targeting IL-6 are available, such as tocilizumab (TCZ), the first IL-6-targeted biologic approved for the treatment of various inflammatory diseases (including rheumatoid arthritis and systemic arthritis). TCZ inhibits IL-6 signaling through targeted binding to IL-6Rα [122]. Currently, there are four potential extracellular targets: the IL-6 signaling pathway, IL-6R, gp130, and IL-6/sIL-6R complexes [123]. However, the application of this method to detect whether OD has recovered or can be improved during the course of treatment has not yet been reported. No drugs have been used to treat OD-related diseases, and further studies are needed to determine whether drugs that inhibit IL-6 can be used for the clinical treatment of OD. In a study of allergic rhinitis (AR) with OD, our team found that the inhibition of IL-6 in an OD model may improve OD [46]. IL-6 can affect nerve regeneration in olfaction, therefore, whether IL-6 can be combined with stem cells to treat OD, as well as gene editing technology and cell therapy, are also directions for future research.

At the same time, we also acknowledge that there are still many shortcomings in the current research status of IL-6, such as the lack of a unified cutoff value, and the lack of differentiation in expression based on race and gender. As age increases, changes in olfactory related anatomical structures and functional degradation of the olfactory nerve can also cause olfactory decline [124]. It is currently unclear whether these olfactory disorders are accompanied by changes in IL-6, so it is more worthwhile for us to further establish a prospective cohort study for further exploration. Of course, it cannot be said that a single marker can determine all aspects of diagnosis. In the future, combining IL-6 with UPSIT testing is likely to demonstrate greater advantages. However, the economic implications of such combined testing must also be considered, and thus, the balance must be sought in clinical practice. We expect that with the deepening of research and development of technology, we will find more therapeutic approaches targeting IL-6, which will bring about better therapeutic effects and quality of life for OD patients.

Conflicts of Interest

The authors declare no conflicts of interest

Author Contributions

Xi-Cheng Song, Chao Ren conceptualize the manuscript topic and provide administrative support; Xiao-Yu Song, Ya-Kui Mou originally drafted the manuscript and summerized the related papers; Han-Rui Wang, Wan-Chen Liu, Yao Wang designed and summarized the tables; Xiao-Yu Song, Han-Rui Wang, Cai-Yu Sun, Ting Yang designed the figures; Xi-Cheng Song, Chao Ren reviewed and revised the manuscript. All authors have read and agreed to the submitted version of the manuscript. Xiao-Yu Song and Ya-Kui Mou contributed equally to this work. Ya-Kui Mou is the co-first author.

Funding

This work was supported by the National Natural Science Foundation of China (82371119, 82271146, 82071021); the Key Research and Development Program of Shandong Province (Major Science and Technology Innovation Project: 2020CXGC011302, 2022CXGC020506; Competitive Innovation Platform Project: 2024CXPT091); the Taishan Scholar Project (NO. tsqn202312392, ts20190991); Shandong Provincial Postdoctoral Foundation Project (Innovation Project: SDCX-ZG-202203077); Science and Technology Innovation development plan of Yantai (2023ZDCX033, 2023JCYJ066); the Outstanding Young Talents Project in Health of Qilu and the youth talent training program from Qingdao medical college of Qingdao University (No. RZ2300002690); Shandong Natural Science Foundation Youth Foundation (ZR2024MH034).