IL-33: biological properties, functions, and roles in airway disease

Abstract

Interleukin (IL)-33 is a key cytokine involved in type 2 immunity and allergic airway diseases. Abundantly expressed in lung epithelial cells, IL-33 plays critical roles in both innate and adaptive immune responses in mucosal organs. In innate immunity, IL-33 and group 2 innate lymphoid cells (ILC2s) provide an essential axis for rapid immune responses and tissue homeostasis. In adaptive immunity, IL-33 interacts with dendritic cells, Th2 cells, follicular T cells, and regulatory T cells, where IL-33 influences the development of chronic airway inflammation and tissue remodeling. The clinical findings that both the IL-33 and ILC2 levels are elevated in patients with allergic airway diseases suggest that IL-33 plays an important role in the pathogenesis of these diseases. IL-33 and ILC2 may also serve as biomarkers for disease classification and to monitor the progression of diseases. In this article, we reviewed the current knowledge of the biology of IL-33 and discussed the roles of the IL-33 in regulating airway immune responses and allergic airway diseases.

Keywords: IL-33; ILC2s; Th2 cells; asthma; rhinosinusitis; type 2 immunity.

Figure 1

The structure of IL-33 and mechanisms of its extracellular release. Panel A. Human IL-33 protein is composed of two evolutionary conserved domains (the nuclear domain and the cytokine domain) that are separated by the highly divergent central domain. Chromatin-binding motif and cleavage sites for inflammatory and apoptotic proteases are indicated. CathG; cathepsin G, NE; neutrophil elastase. Panel B. Proposed mechanisms for extracellular IL-33 release. IL-33 that are constitutively produced and stored in the nucleus is passively released during necrosis when cells lose integrity of plasma and nuclear membrane. Upon apoptosis, IL-33 is retained within the cells and inactivated by apoptotic proteases, such as caspase 3 and caspase 7. Alternatively, cellular stress that is caused by exposure to enviromental factors, such as proteases and ATP, induces cellular activation and post-translational modification of nuclear IL-33 to remove the nuclear domain and central domain. The processed IL-33 is most likely actively secreted extracellularly by structural cells.

Figure 2

The roles of epithelial IL-33 in mucosal immune responses. Exposure to allergens, microbes and perhaps environmetal stress induces IL-33 release from airway epithelial cells. IL-33 activates the innate immune cells, including ILC2s, basophils, eosinophils, and mast cells to drive type 2 inflammation. IL-33 also activates DCs and CD4⁺ T cells and drives proliferation and differentiation of Th2, Tfh and Treg cells and production of antibody by B cells. Note that a bidirectional cross-talk exists betewen the cells involved in the innate immunity and adaptive immunity. Chronic activation of these immune responses results in changes in structural cells, such as epithelial cells, fibroblasts and endotherial cells, and promotes tissue repiar and remodeling. Fibro; fibroblasts, Endo; endothelial cells, Eos; eosinophils, and Baso; basophils.