IL-36 Cytokines: Their Roles in Asthma and Potential as a Therapeutic

Abstract

Interleukin (IL)-36 cytokines are members of the IL-1 superfamily, which consists of three agonists (IL-36α, IL-36β and IL-36γ) and an IL-36 receptor antagonist (IL-36Ra). IL-36 cytokines are crucial for immune and inflammatory responses. Abnormal levels of IL-36 cytokine expression are involved in the pathogenesis of inflammation, autoimmunity, allergy and cancer. The present study provides a summary of recent reports on IL-36 cytokines that participate in the pathogenesis of inflammatory diseases, and the potential mechanisms underlying their roles in asthma. Abnormal levels of IL-36 cytokines are associated with the pathogenesis of different types of asthma through the regulation of the functions of different types of cells. Considering the important role of IL-36 cytokines in asthma, these may become a potential therapeutic target for asthma treatment. However, existing evidence is insufficient to fully elucidate the specific mechanism underlying the action of IL-36 cytokines during the pathological process of asthma. The possible mechanisms and functions of IL-36 cytokines in different types of asthma require further studies.

Keywords: IL-36; asthma; inflammation; phenotype; therapeutic agent.

Figure 1

The production of IL-36 cytokines and the downstream signaling network. IL-36 can bind to IL-36R on a variety of cells (such as keratinocytes, dendritic cells, T cells, eosinophils, PBMCs and macrophages) through different signaling pathways to produce cytokines and chemokines, and promote neutrophil and eosinophil infiltration, T cell proliferation and macrophage polarization, in order to promote inflammation. However, IL-36Ra acts as an antagonist of IL-36R without activating the downstream signaling.

Figure 2

The potential roles of IL-36 cytokines in asthma. IL-36 cytokines promote Th1, Th17 and Th9 differentiation, and inhibit iTreg differentiation. These also enhance the production of cytokines and chemokines through lung epithelial cells, fibroblasts and macrophages, and promote neutrophil and eosinophil inflammation to participate in the pathogenesis of various subtypes of asthma. Neutrophil degranulation or NET-derived proteases can promote IL-36 cytokine cleavage, thereby promoting inflammatory response. IL-36 cytokines can also regulate autophagy and NLRP3, but the specific roles in asthma remain to be elucidated. IL-36Ra can reduce the production of cytokines, AHR and airway inflammation, and the inflammatory response of asthma.