Exploring the immune-modulating properties of boswellic acid in experimental autoimmune encephalomyelitis
Alireza Shadab
Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
Deputy of Health, Iran University of Medical Sciences, Tehran, Iran
Search for more papers by this authorMohammad Abbasi-Kolli
Deputy of Health, Iran University of Medical Sciences, Tehran, Iran
Search for more papers by this authorEsmaeil Yazdanpanah
Immunology Research Center, and Department of Immunology, Mashhad University of Medical Sciences, Mashhad, Iran
Search for more papers by this authorSeyed-Alireza Esmaeili
Immunology Research Center, and Department of Immunology, Mashhad University of Medical Sciences, Mashhad, Iran
Search for more papers by this authorRasoul Baharlou
Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
Search for more papers by this authorBahman Yousefi
Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
Search for more papers by this authorCorresponding Author
Dariush Haghmorad
Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
Dariush Haghmorad, Semnan University of Medical Sciences, Semnan, Iran. e-mail: [email protected]
Search for more papers by this authorAlireza Shadab
Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
Deputy of Health, Iran University of Medical Sciences, Tehran, Iran
Search for more papers by this authorMohammad Abbasi-Kolli
Deputy of Health, Iran University of Medical Sciences, Tehran, Iran
Search for more papers by this authorEsmaeil Yazdanpanah
Immunology Research Center, and Department of Immunology, Mashhad University of Medical Sciences, Mashhad, Iran
Search for more papers by this authorSeyed-Alireza Esmaeili
Immunology Research Center, and Department of Immunology, Mashhad University of Medical Sciences, Mashhad, Iran
Search for more papers by this authorRasoul Baharlou
Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
Search for more papers by this authorBahman Yousefi
Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
Search for more papers by this authorCorresponding Author
Dariush Haghmorad
Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran
Cancer Research Center, Semnan University of Medical Sciences, Semnan, Iran
Dariush Haghmorad, Semnan University of Medical Sciences, Semnan, Iran. e-mail: [email protected]
Search for more papers by this authorAbstract
Multiple sclerosis (MS) is a condition where the central nervous system loses its myelin coating due to autoimmune inflammation. The experimental autoimmune encephalomyelitis (EAE) simulates some aspects of human MS. Boswellic acids are natural compounds derived from frankincense extract, known for their anti-inflammatory properties. The purpose of this research was to investigate therapeutic potential of boswellic acids. Mice were divided into three groups: low-dose (LD), high-dose (HD), and control groups (CTRL). Following EAE induction, the mice received daily doses of boswellic acid for 25 days. Brain tissue damage, clinical symptoms, and levels of TGF-β, IFN-γ, and IL-17 cytokines in cell cultured supernatant of lymphocytes were assessed. Gene expression of transcription factors in brain was measured using real-time PCR. The levels of brain demyelination were significantly lower in the treatment groups compared to the CTRL group. Boswellic acid reduced the severity and duration of EAE symptoms. Furthermore, boswellic acid decreased the amounts of IFN-γ and IL-17, also the expression of T-bet and ROR-γt in brain. On the contrary, it increased the levels of TGF-β and the expression FoxP3 and GATA3. Our findings suggest that boswellic acids possess therapeutic potential for EAE by modulating the immune response and reducing inflammation.
CONFLICT OF INTEREST
The authors declare no financial or commercial conflict of interest. The authors alone are responsible for the content of this manuscript.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
REFERENCES
- 1Berek K, Bauer A, Rudzki D, Auer M, Barket R, Zinganell A, et al. Immune profiling in multiple sclerosis: a single-center study of 65 cytokines, chemokines, and related molecules in cerebrospinal fluid and serum. Front Immunol. 2023; 14:1200146.
- 2Yadav SK, Mindur JE, Ito K, Dhib-Jalbut S. Advances in the immunopathogenesis of multiple sclerosis. Curr Opin Neurol. 2015; 28(3): 206–219.
- 3Meyer-Arndt L, Kerkering J, Kuehl T, Infante AG, Paul F, Rosiewicz KS, et al. Inflammatory cytokines associated with multiple sclerosis directly induce alterations of neuronal cytoarchitecture in human neurons. J Neuroimmune Pharmacol. 2023; 18: 145–159.
- 4Peruzzotti-Jametti L, Donegá M, Giusto E, Mallucci G, Marchetti B, Pluchino S. The role of the immune system in central nervous system plasticity after acute injury. Neuroscience. 2014; 283: 210–221.
- 5Fournier AP, Zandee S, Charabati M, Peelen E, Tastet O, Alvarez JI, et al. CLMP promotes leukocyte migration across brain barriers in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2022; 9(6):e200022.
- 6Nissen JC, Tsirka SE. Preclinical model of multiple sclerosis: methods in autoimmune demyelination. Methods Cell Biol. 2022; 168: 67–86.
- 7Weissert R. Actively induced experimental autoimmune encephalomyelitis in rats. Methods Mol Biol. 2016; 1304: 161–169.
- 8Ansari MA, Nadeem A, Alshammari MA, Attia SM, Bakheet SA, Khan MR, et al. Cathepsin B inhibitor alleviates Th1, Th17, and Th22 transcription factor signaling dysregulation in experimental autoimmune encephalomyelitis. Exp Neurol. 2022; 351:113997.
- 9Al-Mazroua HA, Nadeem A, Ansari MA, Attia SM, Bakheet SA, Albekairi TH, et al. CCR1 antagonist ameliorates experimental autoimmune encephalomyelitis by inhibition of Th9/Th22-related markers in the brain and periphery. Mol Immunol. 2022; 144: 127–137.
- 10Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Alasmari AF, Shahid M, et al. MAP kinase inhibitor PD98059 regulates Th1, Th9, Th17, and natural T regulatory cells in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Eur J Pharmacol. 2023; 959:176086.
- 11Huang D-L, He Y-R, Liu Y-J, He H-Y, Gu Z-Y, Liu Y-M, et al. The immunomodulation role of Th17 and Treg in renal transplantation. Front Immunol. 2023; 14:1113560.
- 12Eken A, Erdem S, Haliloglu Y, Zehra Okus F, Cakir M, Fatih Yetkin M, et al. Temporal overexpression of IL-22 and Reg3γ differentially impacts the severity of experimental autoimmune encephalomyelitis. Immunology. 2021; 164(1): 73–89.
- 13Jiang Y, Wu A, Zhu C, Pi R, Chen S, Liu Y, et al. The protective effect of berberine against neuronal damage by inhibiting matrix metalloproteinase-9 and laminin degradation in experimental autoimmune encephalomyelitis. Neurol Res. 2013; 35(4): 360–368.
- 14Weber CC, Reising K, Müller WE, Schubert-Zsilavecz M, Abdel-Tawab M. Modulation of Pgp function by boswellic acids. Planta Med. 2006; 72(6): 507–513.
- 15Devanand M, Saiprabha VN, Madhu K. Signaling mechanisms involved in the regulation of remyelination in multiple sclerosis: a mini review. J Mol Med (Berl). 2023; 101(6): 637–644.
- 16Zi-Han H, Meng-Hua WU, Si-Min L, Yu Z, Ying Z, Zhi-Guo MA, et al. Herbalogical study on olibanum(Ruxiang). Zhongguo Zhong Yao Za Zhi. 2020; 45(21): 5296–5303.
- 17Nadeem A, Ahmad SF, Al-Harbi NO, Sarawi W, Attia SM, Alanazi WA, et al. Acetyl-11-keto-beta-boswellic acid improves clinical symptoms through modulation of Nrf2 and NF-kappaB pathways in SJL/J mouse model of experimental autoimmune encephalomyelitis. Int Immunopharmacol. 2022; 107:108703.
- 18Bolbolian S, Bozorgmehr MR, Morsali A. Acetyl-11-keto-β-boswellic acid derivatives effects on 5-lipoxygenase: in silico viewpoint. J Mol Graph Model. 2020; 94:107464.
- 19Wang Q, Pan X, Wong HH, Wagner CA, Lahey LJ, Robinson WH, et al. Oral and topical boswellic acid attenuates mouse osteoarthritis. Osteoarthr Cartil. 2014; 22(1): 128–132.
- 20Siemoneit U, Tausch L, Poeckel D, Paul M, Northoff H, Koeberle A, et al. Defined structure-activity relationships of Boswellic acids determine modulation of Ca2+ mobilization and aggregation of human platelets by Boswellia serrata extracts. Planta Med. 2017; 83(12–13): 1020–1027.
- 21Roy NK, Parama D, Banik K, Bordoloi D, Devi AK, Thakur KK, et al. An update on pharmacological potential of Boswellic acids against chronic diseases. Int J Mol Sci. 2019; 20(17):4101.
- 22Karra AG, Tziortziou M, Kylindri P, Georgatza D, Gorgogietas VA, Makiou A, et al. Boswellic acids and their derivatives as potent regulators of glucocorticoid receptor actions. Arch Biochem Biophys. 2020; 695:108656.
- 23Kazemi R, Yazdanpanah E, Esmaeili SA, Yousefi B, Baharlou R, Haghmorad D. Thymoquinone improves experimental autoimmune encephalomyelitis by regulating both pro-inflammatory and anti-inflammatory cytokines. Mol Biol Rep. 2024; 51(1): 256.
- 24Haghmorad D, Khaleghian A, Eslami M, Sadeghnejad A, Tarahomi M, Yousefi B. Bone marrow mesenchymal stem cells to ameliorate experimental autoimmune encephalomyelitis via modifying expression patterns of miRNAs. Mol Biol Rep. 2023; 50(12): 9971–9984.
- 25Ameen AM, Elkazaz AY, Mohammad HMF, Barakat BM. Anti-inflammatory and neuroprotective activity of boswellic acids in rotenone parkinsonian rats. Can J Physiol Pharmacol. 2017; 95(7): 819–829.
- 26Sayed AS, Gomaa IEO, Bader M, El Sayed N. Role of 3-Acetyl-11-keto-Beta-Boswellic acid in counteracting LPS-induced neuroinflammation via modulation of miRNA-155. Mol Neurobiol. 2018; 55(7): 5798–5808.
- 27Ebrahimpour S, Fazeli M, Mehri S, Taherianfard M, Hosseinzadeh H. Boswellic acid improves cognitive function in a rat model through its antioxidant activity: - neuroprotective effect of Boswellic acid. J Pharm. 2017; 20(1): 10–17.
- 28Sayed AS, El Sayed NS. Co-administration of 3-Acetyl-11-keto-Beta-Boswellic acid potentiates the protective effect of celecoxib in lipopolysaccharide-induced cognitive impairment in mice: possible implication of anti-inflammatory and Antiglutamatergic pathways. J Mol Neurosci. 2016; 59(1): 58–67.
- 29Haghmorad D, Yazdanpanah E, Sadighimoghaddam B, Yousefi B, Sahafi P, Ghorbani N, et al. Kombucha ameliorates experimental autoimmune encephalomyelitis through activation of Treg and Th2 cells. Acta Neurol Belg. 2021; 121(6): 1685–1692.
- 30Amiri Z, Jalili S, Tarahomi M, Eslami M, Yazdanpanah E, Baharlou R, et al. Curcumin's spice-infused therapeutic promise: disease severity alleviation in a mouse model of multiple sclerosis via modulation of immune responses. Mol Biol Rep. 2023; 50(11): 8843–8853.
- 31Alvarez-Sanchez N, Dunn SE. Immune cell contributors to the female sex bias in multiple sclerosis and experimental autoimmune encephalomyelitis. Curr Top Behav Neurosci. 2023; 62: 333–373.
- 32Pachner A. The brave New World of early treatment of multiple sclerosis: using the molecular biomarkers CXCL13 and neurofilament light to optimize immunotherapy. Biomedicine. 2022; 10(9):2099.
- 33Hamidpour R, Hamidpour S, Hamidpour M, Shahlari M. Frankincense (rǔ xiāng; boswellia species): from the selection of traditional applications to the novel phytotherapy for the prevention and treatment of serious diseases. J Tradit Complement Med. 2013; 3(4): 221–226.
- 34Rajabian A, Sadeghnia H, Fanoudi S, Hosseini A. Genus Boswellia as a new candidate for neurodegenerative disorders. Iran J Basic Med Sci. 2020; 23(3): 277–286.
- 35Ammon HPT. Boswellic extracts and 11-keto-ß-boswellic acids prevent type 1 and type 2 diabetes mellitus by suppressing the expression of proinflammatory cytokines. Phytomedicine. 2019; 63:153002.
- 36Chen L, Bai J, Peng D, Gao Y, Cai X, Zhang J, et al. SZB120 exhibits immunomodulatory effects by targeting eIF2α to suppress Th17 cell differentiation. J Immunol. 2021; 206(5): 953–962.
- 37Stürner KH, Verse N, Yousef S, Martin R, Sospedra M. Boswellic acids reduce Th17 differentiation via blockade of IL-1β-mediated IRAK1 signaling. Eur J Immunol. 2014; 44(4): 1200–1212.
- 38Khan MA, Ali R, Parveen R, Najmi AK, Ahmad S. Pharmacological evidences for cytotoxic and antitumor properties of Boswellic acids from Boswellia serrata. J Ethnopharmacol. 2016; 191: 315–323.
- 39Ansari MA, Nadeem A, Attia SM, Bakheet SA, Shahid M, Rehman MU, et al. CCR1 antagonist J-113863 corrects the imbalance of pro- and anti-inflammatory cytokines in a SJL/J mouse model of relapsing-remitting multiple sclerosis. Immunobiology. 2022; 227(5):152245.
- 40Roederer M, Quaye L, Mangino M, Beddall MH, Mahnke Y, Chattopadhyay P, et al. The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis. Cell. 2015; 161(2): 387–403.
- 41Zhou F, Chen F, Ouyang Z, Zhu R, Zhou R, Hu W, et al. Functions of peroxiredoxins and their roles in autoimmune diseases. Antioxid Redox Signal. 2023; 40: 329–344.
- 42Peng Y, Deng X, Zeng Q, Tang Y. Tc17 cells in autoimmune diseases. Chin Med J (Engl). 2022; 135(18): 2167–2177.
- 43Rabe SZT, Sahebari M, Mahmoudi Z, Hosseinzadeh H, Haghmorad D, Tabasi N, et al. Inhibitory effect of Crocus sativus L. ethanol extract on adjuvant-induced arthritis. Food Agr Immunol. 2015; 26(2): 170–180.
- 44Barnett MH, Mathey E, Kiernan MC, Pollard JD. Axonal damage in central and peripheral nervous system inflammatory demyelinating diseases: common and divergent pathways of tissue damage. Curr Opin Neurol. 2016; 29(3): 213–221.
- 45Zhao J, Liao Y, Miller-Little W, Xiao J, Liu C, Li X, et al. STEAP4 expression in CNS resident cells promotes Th17 cell-induced autoimmune encephalomyelitis. J Neuroinflammation. 2021; 18(1): 98.
- 46Wang W, Thomas R, Oh J, Su DM. Accumulation of pTreg cells is detrimental in late-onset (aged) mouse model of multiple sclerosis. Aging Cell. 2022; 21(6):e13630.
- 47Ahmad SF, Ansari MA, Nadeem A, Bakheet SA, Al-Mazroua HA, Alomar HA, et al. S3I-201, a selective stat3 inhibitor, ameliorates clinical symptoms in a mouse model of experimental autoimmune encephalomyelitis through the regulation of multiple intracellular signalling in Th1, Th17, and treg cells. Mult Scler Relat Disord. 2023; 73:104658.
- 48Zhu X, Wang P, Zhan X, Zhang Y, Sheng J, He S, et al. USP1-regulated reciprocal differentiation of Th17 cells and Treg cells by deubiquitinating and stabilizing TAZ. Cell Mol Immunol. 2023; 20(3): 252–263.
- 49Lee GR. The balance of Th17 versus Treg cells in autoimmunity. Int J Mol Sci. 2018; 19(3):730.