The role of interleukin-33 in the pathogenesis, and treatment of severe asthma

Abstract

Interleukin-33 (IL-33) belongs to the IL-1 family of cytokines, which has 11 members, including IL-1α, IL-1β, IL-1Ra, IL-18, IL-36α, IL-36β, and IL-37. Unlike its family members, IL-33 mediates T helper type-2 (Th2) immune responses, and promotes eosinophilic inflammation, similar to the other epithelial-derived cytokines, such as IL-25, and thymic stromal lymphopoietin (TSLP). Epithelial injury due to viral, and bacterial infections, allergens, chemical irritants, and trauma lead to secretion of alarmin cytokines, including IL-25, IL-33, and TSLP. IL-33 plays an important role in activating Th2 lymphocytes, group 2 innate lymphoid cells, dendritic cells, mast cells, basophils, and eosinophils, which result in secretion of cytokines, such as IL-4, IL-13, and IL-5; chemokines, including CCL2, and CXCL8, and adhesion molecules. The inflammatory mediators promote eosinophilic airway inflammation, airway hyperresponsiveness, and remodeling. IL-33 signaling is via a complex heterodimeric receptor comprising of IL-1 receptor-like 1 (IL-1RL1), and IL-1 receptor accessory protein. Downstream signaling cascade leads to the transcription of multiple cytokines and chemokines, which orchestrate eosinophilic asthma. Treatment of severe eosinophilic asthma include long-acting beta2-agonists, and inhaled corticosteroids, and addition of biologics at GINA step 4/5, such as omalizumab, mepolizumab, dupilumab, and tezepelumab. Currently, there are no anti-IL-33 biologics which have been approved for the treatment of eosinophilic asthma. Etokimab is a first-in-class IgG1 monoclonal antibody which blocks the activity of IL-33, thereby, inhibiting its biological effects. Phase 2a proof-of-concept clinical trial in 25 patient with severe eosinophilic asthma, showed that a single intravenous dose of etokimab (330 mg) resulted in a rapid and sustained improvement in lung function, and reduction in the asthma control questionnaire-5 scores throughout the study period of 64 days. Recently, itepekimab has been shown to improve asthma control, lung function, and quality of life, although the effects of itepekimab were slightly lesser than those observed for dupilumab. The dual therapy of itepekimab plus dupilumab did not achieve optimal outcomes, moreover, treatment with the doublet resulted in minimal change in pre-bronchodilator FEV1 compared with placebo. Dual blockade of interleukins incriminated in the pathogenesis of eosinophilic asthma need further careful studies, because of the immunological consequences in the era of SARS-CoV-2.