IL33: Roles in Allergic Inflammation and Therapeutic Perspectives

Abstract

Interleukin (IL)-33 belongs to IL-1 cytokine family which is constitutively produced from the structural and lining cells including fibroblasts, endothelial cells, and epithelial cells of skin, gastrointestinal tract, and lungs that are exposed to the environment. Different from most cytokines that are actively secreted from cells, nuclear cytokine IL-33 is passively released during cell necrosis or when tissues are damaged, suggesting that it may function as an alarmin that alerts the immune system after endothelial or epithelial cell damage during infection, physical stress, or trauma. IL-33 plays important roles in type-2 innate immunity via activation of allergic inflammation-related eosinophils, basophils, mast cells, macrophages, and group 2 innate lymphoid cells (ILC2s) through its receptor ST2. In this review, we focus on the recent advances of the underlying intercellular and intracellular mechanisms by which IL-33 can regulate the allergic inflammation in various allergic diseases including allergic asthma and atopic dermatitis. The future pharmacological strategy and application of traditional Chinese medicines targeting the IL-33/ST2 axis for anti-inflammatory therapy of allergic diseases were also discussed.

Keywords: Chinese herbal medicine; IL-33; allergic inflammation; eosinophils; innate lymphoid cells (ILC); mast cells; signal transduction; therapeutics.

Figure 1

Effects of IL-33 on the activation of eosinophils, basophils, mast cells, DCs, ILC2 cells, and T cells in allergic inflammation. IL-33 is normally sequestered in the nucleus of various cells via nuclear-localization and chromatin-binding motifs in its amino terminus. After the cells are damaged, under stress, or stimulated by allergens, full-length IL-33 is released extracellularly, but it has low activity as a cytokine. Mast cells proteases and some allergens possess protease activity and can directly process IL-33 by cleaving within the protease-sensor domain to generate a more potent cytokine domain, which will directly activate local and infiltrating basophils, mast cells, group 2 innate lymphoid cells (ILC2), T cells, and eosinophils to induce allergic inflammation.