Crucial and diverse role of the interleukin-33/ST2 axis in infectious diseases

Abstract

Interleukin-33 (IL-33) has now emerged as a cytokine with diverse and pleiotropic functions in various infectious and inflammatory diseases. IL-33 is expressed by epithelial cells, endothelial cells, fibroblasts, and hepatocytes. The target cells of IL-33 are Th2 cells, basophils, dendritic cells, mast cells, macrophages, NKT cells, and nuocytes, newly discovered natural helper cells/innate lymphoid cells bearing the ST2 receptor. IL-33 has dual functions, both as a traditional cytokine and as a nuclear factor that regulates gene transcription. IL-33 functions as an "alarmin" released following cell death, as a biomarker, and as a vaccine adjuvant, with proinflammatory and protective effects during various infections. The exacerbated or protective role of the IL-33/ST2 axis during different infections is dependent upon the organ involved, type of infectious agent, whether the infection is acute or chronic, the invasiveness of the infectious agent, the host immune compartment, and cellular and cytokine microenvironments. In this review, we focus on recent advances in the understanding of the role of the IL-33/ST2 axis in various viral, bacterial, fungal, helminth, and protozoal infectious diseases gained from animal models and studies in human patients. The functional role of IL-33 and ST2 during experimentally induced infections has been summarized by accumulating the data for IL-33- and ST2-deficient mice or for mice exogenously administered IL-33. In summary, exploring the crucial and diverse roles of the IL-33/ST2 axis during infections may help in the development of therapeutic interventions for a wide range of infectious diseases.

FIG 1

Diverse role of the IL-33/ST2 axis during microbial infections. The alarmin cytokine IL-33 is released during viral, bacterial, fungal, and parasitic infections of host cells or during cellular demise. IL-33 interacts with ST2-bearing immune cells to induce secretion of various cytokines. IL-33/ST2 signaling is mediated by the MyD88/mitogen-activated protein kinase/NF-κB pathway. The IL-33/ST2 axis plays a dual-edge function, as it either is protective, for example, in RSV, influenza virus, herpes simplex virus, coxsackie B virus, LCMV, HBV, septic shock (LPS, BLP), keratitis (P. aeruginosa), dermatitis (S. aureus), peritonitis (C. albicans), or blood microfilaria (L. sigmodontis) infections, or has an exacerbating role in Th2-biased lung mycosis (C. neoformans), fungal asthma (A. alternata), lung infection (S. mansoni, N. brasiliensis), brain infection (A. cantonesis), or intestinal infections (T. muris, T. spiralis). At the nucleus level, IL-33 acts also as a transcription repressor. DAMPs, damage-associated molecular patterns; PAMPs, pathogen-associated molecular patterns.