Iranian Journal of Immunology

Effects of Blocking NLRP3 Inflammasome on Type II Innate Lymphoid Cell Response in Allergic Rhinitis

Document Type : Original Article

Authors

Guoqing Gong
Peng Huang
Changliang Yang
Chengcheng Huang
Zhao Zhang
Ruiyao Chen
Tingfeng Sun
Guang Yang

Department of Otolaryngology, General Hospital of Central Theater Command, Wuhan, Hubei, China.

https://doi.org/10.22034/iji.2023.96966.2473
Abstract
Background: Type 2 innate lymphoid cells (ILC2s) and NLRP3 inflammasome are related to allergic and inflammatory responses. NLRP3 inflammasome inhibitor MCC950 was demonstrated to ameliorate allergic rhinitis (AR) in animal models.
Objective: To elucidate the effect of MCC950 on ILC2 responses in AR.
Methods: NLRP3 inflammasome, ILC2s, IL-5+ILC2s, IL-13+ILC2s, and Th2-related factors were examined in 30 AR patients. ILC2s were identified as Lin-CRTH2+CD127+lymphocytes. ILC2s isolated from PBMCs were stimulated with LPS plus ATP. The effect of MCC950, IL-1β, and IL-18 on ILC2 responses was detected by flow cytometry. AR models were established in 60 BALB/c mice. Nasal symptoms and ILC2 responses in the AR models after MCC950 treatment were detected. Human nasal epithelial cells were stimulated with IL-13 (10 ng/mL) and treated with MCC950 (10 μM).
Results: AR patients showed activated NLRP3 inflammasome and increased ILC2 responses compared to controls. NLRP3 inflammasome levels in the AR patients were positively related to the proportion of ILC2s, IL-5+ILC2s, and IL-13+ILC2s in total PBMCs. MCC950 treatment or IL-1β/IL-18 suppression inhibited ILC2 proliferation and Th2-related factors (GATA3, RORα, IL-5, and IL-13). MCC950 administration alleviated frequencies of nasal rubbing and sneezes in the AR models. ILC2s, IL-5+ILC2s, and IL-13+ILC2s in mice were reduced by MCC950. MCC950 inhibited NLRP3 inflammasome in the in vitro models of AR.
Conclusion: MCC950 inhibited ILC2 responses in AR and mice models, suggesting that blocking NLRP3 inflammasome may be a promising target for AR clinical treatment.

Keywords

Allergic Rhinitis
MCC950
NLRP3 Inflammasome
Type II Innate Lymphoid Cell
  1. Schuler Iv CF, Montejo JM. Allergic Rhinitis in Children and Adolescents. Pediatr Clin North Am. 2019;66(5):981-93.
  2. Thiriou D, Morianos I, Xanthou G, Samitas K. Innate immunity as the orchestrator of allergic airway inflammation and resolution in asthma. International immunopharmacology. 2017;48:43-54.
  3. Eifan AO, Durham SR. Pathogenesis of rhinitis. Clin Exp Allergy. 2016;46(9):1139-51.
  4. Kabata H, Moro K, Koyasu S. The group 2 innate lymphoid cell (ILC2) regulatory network and its underlying mechanisms. Immunol Rev. 2018;286(1):37-52.
  5. Dhariwal J, Edwards MR, Johnston SL. Anti-viral agents: potential utility in exacerbations of asthma. Curr Opin Pharmacol. 2013;13(3):331-6.
  6. Zhong H, Fan XL, Yu QN, Qin ZL, Chen D, Xu R, et al. Increased innate type 2 immune response in house dust mite-allergic patients with allergic rhinitis. Clin Immunol. 2017;183:293-9.
  7. Lin L, Dai F, Wei JJ, Tang XY, Chen Z, Sun GB. Allergic inflammation is exacerbated by allergen-induced type 2 innate lymphoid cells in a murine model of allergic rhinitis. Rhinology. 2017;55(4):339-47.
  8. De Nardo D, Latz E. NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol. 2011;32(8):373-9.
  9. Wan H, Su H, Wu Y, Zhao Y, Zhou M. [Expression and significance of NLRP3 inflammasome and its downstream factors IL-1β/IL-18 in rat model of allergic rhinitis]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2015;50(2):145-50.
  10. Zhang W, Ba G, Tang R, Li M, Lin H. Ameliorative effect of selective NLRP3 inflammasome inhibitor MCC950 in an ovalbumin-induced allergic rhinitis murine model. Int Immunopharmacol. 2020;83:106394.
  11. Kato A. Group 2 Innate Lymphoid Cells in Airway Diseases. Chest. 2019;156(1):141-9.
  12. Martinez-Gonzalez I, Ghaedi M, Steer CA, Mathä L, Vivier E, Takei F. ILC2 memory: Recollection of previous activation. Immunol Rev. 2018;283(1):41-53.
  13. Simoni Y, Fehlings M, Kløverpris HN, McGovern N, Koo SL, Loh CY, et al. Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency. Immunity. 2017;46(1):148-61.
  14. Bal SM, Bernink JH, Nagasawa M, Groot J, Shikhagaie MM, Golebski K, et al. IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat Immunol. 2016;17(6):636-45.
  15. Ohne Y, Silver JS, Thompson-Snipes L, Collet MA, Blanck JP, Cantarel BL, et al. IL-1 is a critical regulator of group 2 innate lymphoid cell function and plasticity. Nat Immunol. 2016;17(6):646-55.
  16. He Y, Hara H, Núñez G. Mechanism and Regulation of NLRP3 Inflammasome Activation. Trends Biochem Sci. 2016;41(12):1012-21.
  17. Durham SR, Creticos PS, Nelson HS, Li Z, Kaur A, Meltzer EO, et al. Treatment effect of sublingual immunotherapy tablets and pharmacotherapies for seasonal and perennial allergic rhinitis: Pooled analyses. J Allergy Clin Immunol. 2016;138(4):1081-8.e4.
  18. Shamji MH, Layhadi JA, Achkova D, Kouser L, Perera-Webb A, Couto-Francisco NC, et al. Role of IL-35 in sublingual allergen immunotherapy. J Allergy Clin Immunol. 2019;143(3):1131-42.e4.
  19. Erster O, Mendelson E, Levy V, Kabat A, Mannasse B, Asraf H, et al. Rapid and High-Throughput Reverse Transcriptase Quantitative PCR (RT-qPCR) Assay for Identification and Differentiation between SARS-CoV-2 Variants B.1.1.7 and B.1.351. Microbiology spectrum. 2021:e0050621.
  20. Lin H, Zheng C, Li J, Yang C, Hu L. Lentiviral shRNA against KCa3.1 inhibits allergic response in allergic rhinitis and suppresses mast cell activity via PI3K/AKT signaling pathway. Sci Rep. 2015;5:13127.
  21. Suzuki M, Yokota M, Ozaki S, Matsumoto T. Intranasal Administration of IL-27 Ameliorates Nasal Allergic Responses and Symptoms. Int Arch Allergy Immunol. 2019;178(2):101-5.
  22. Xiao Y, Xu W, Su W. NLRP3 inflammasome: A likely target for the treatment of allergic diseases. Clin Exp Allergy. 2018;48(9):1080-91.
  23. Zahid A, Li B, Kombe AJK, Jin T, Tao J. Pharmacological Inhibitors of the NLRP3 Inflammasome. Front Immunol. 2019;10:2538.
  24. Nachmias N, Langier S, Brzezinski RY, Siterman M, Stark M, Etkin S, et al. NLRP3 inflammasome activity is upregulated in an in-vitro model of COPD exacerbation. PLoS One. 2019;14(5):e0214622.
  25. Gordon EM, Yao X, Xu H, Karkowsky W, Kaler M, Kalchiem-Dekel O, et al. Apolipoprotein E is a concentration-dependent pulmonary danger signal that activates the NLRP3 inflammasome and IL-1β secretion by bronchoalveolar fluid macrophages from asthmatic subjects. J Allergy Clin Immunol. 2019;144(2):426-41.e3.
  26. Wu D, Chen Y, Sun Y, Gao Q, Li H, Yang Z, et al. Target of MCC950 in Inhibition of NLRP3 Inflammasome Activation: a Literature Review. Inflammation. 2020;43(1):17-23.
  27. Lin H, Li Z, Lin D, Zheng C, Zhang W. Role of NLRP3 Inflammasome in Eosinophilic and Non-eosinophilic Chronic Rhinosinusitis with Nasal Polyps. Inflammation. 2016;39(6):2045-52.
  28. Xu M, Wang L, Wang M, Wang H, Zhang H, Chen Y, et al. Mitochondrial ROS and NLRP3 inflammasome in acute ozone-induced murine model of airway inflammation and bronchial hyperresponsiveness. Free Radic Res. 2019;53(7):780-90.
  29. Liu X, Shen J, Fan D, Qiu X, Guo Q, Zheng K, et al. Yupingfeng San Inhibits NLRP3 Inflammasome to Attenuate the Inflammatory Response in Asthma Mice. Front Pharmacol. 2017;8:944.
  30. Chen S, Yao L, Huang P, He Q, Guan H, Luo Y, et al. Blockade of the NLRP3/Caspase-1 Axis Ameliorates Airway Neutrophilic Inflammation in a Toluene Diisocyanate-Induced Murine Asthma Model. Toxicol Sci. 2019;170(2):462-75.
  31. Wang L, Zha B, Shen Q, Zou H, Cheng C, Wu H, et al. Sevoflurane Inhibits the Th2 Response and NLRP3 Expression in Murine Allergic Airway Inflammation. J Immunol Res. 2018;2018:9021037.
  32. Coll RC, Robertson AA, Chae JJ, Higgins SC, Muñoz-Planillo R, Inserra MC, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21(3):248-55.
  33. Gao R, Shi H, Chang S, Gao Y, Li X, Lv C, et al. The selective NLRP3-inflammasome inhibitor MCC950 reduces myocardial fibrosis and improves cardiac remodeling in a mouse model of myocardial infarction. Int Immunopharmacol. 2019;74:105575.
  34. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464(7293):1367-70.
  35. Doherty TA, Scott D, Walford HH, Khorram N, Lund S, Baum R, et al. Allergen challenge in allergic rhinitis rapidly induces increased peripheral blood type 2 innate lymphoid cells that express CD84. J Allergy Clin Immunol. 2014;133(4):1203-5.
  36. Bartemes KR, Kephart GM, Fox SJ, Kita H. Enhanced innate type 2 immune response in peripheral blood from patients with asthma. The Journal of allergy and clinical immunology. 2014;134(3):671-8.e4.
  37. Boraschi D, Dinarello CA. IL-18 in autoimmunity: review. Eur Cytokine Netw. 2006;17(4):224-52.
  38. Yoshizawa Y, Nomaguchi H, Izaki S, Kitamura K. Serum cytokine levels in atopic dermatitis. Clin Exp Dermatol. 2002;27(3):225-9.
  39. Ando M, Shima M. Serum interleukins 12 and 18 and immunoglobulin E concentrations and allergic symptoms in Japanese schoolchildren. Journal of investigational allergology & clinical immunology. 2007;17(1):14-9.
  40. Tanaka H, Miyazaki N, Oashi K, Teramoto S, Shiratori M, Hashimoto M, et al. IL-18 might reflect disease activity in mild and moderate asthma exacerbation. J Allergy Clin Immunol. 2001;107(2):331-6.
  41. Sugimoto T, Ishikawa Y, Yoshimoto T, Hayashi N, Fujimoto J, Nakanishi K. Interleukin 18 acts on memory T helper cells type 1 to induce airway inflammation and hyperresponsiveness in a naive host mouse. J Exp Med. 2004;199(4):535-45.
  42. Kumano K, Nakao A, Nakajima H, Hayashi F, Kurimoto M, Okamura H, et al. Interleukin-18 enhances antigen-induced eosinophil recruitment into the mouse airways. Am J Respir Crit Care Med. 1999;160(3):873-8.
  43. Kodama T, Matsuyama T, Kuribayashi K, Nishioka Y, Sugita M, Akira S, et al. IL-18 deficiency selectively enhances allergen-induced eosinophilia in mice. J Allergy Clin Immunol. 2000;105(1 Pt 1):45-53.
Iranian Journal of Immunology
Volume 20, Issue 3
Summer 2023
Pages 287-302

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