The ST2/IL-33 Axis in Immune Cells during Inflammatory Diseases

Abstract

Il1rl1 (also known as ST2) is a member of the IL-1 superfamily, and its only known ligand is IL-33. ST2 exists in two forms as splice variants: a soluble form (sST2), which acts as a decoy receptor, sequesters free IL-33, and does not signal, and a membrane-bound form (ST2), which activates the MyD88/NF-κB signaling pathway to enhance mast cell, Th2, regulatory T cell (Treg), and innate lymphoid cell type 2 functions. sST2 levels are increased in patients with active inflammatory bowel disease, acute cardiac and small bowel transplant allograft rejection, colon and gastric cancers, gut mucosal damage during viral infection, pulmonary disease, heart disease, and graft-versus-host disease. Recently, sST2 has been shown to be secreted by intestinal pro-inflammatory T cells during gut inflammation; on the contrary, protective ST2-expressing Tregs are decreased, implicating that ST2/IL-33 signaling may play an important role in intestinal disease. This review will focus on what is known on its signaling during various inflammatory disease states and highlight potential avenues to intervene in ST2/IL-33 signaling as treatment options.

PD‐1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator‐activated receptor‐γ

“…One possible reason for these discrepancies between our study and that of Taylor et al is that we used mice lacking RAG genes and these mice lack both T and B cells that might have feedback effects on ILC. In the study of Taylor et al, IL‐33 could still interact with T cells expressing ST2, which might skew immune responses . In addition, it has been found that IL‐2 can increase IL‐5 and IL‐13 production by ILC2 and IL‐2 would be an abundant cytokine in immunocompetent mice.…”

Prognostic value of soluble ST2 postaortic valve replacement: a meta-analysis

“…For example, the biomarker B-type natriuretic peptide (BNP) is produced in response to pressure overload,16 whereas sST2 is released during chronic inflammation 17. The biomarker sST2 is a member of the IL-1 receptor family with both transmembrane (ST2L) and soluble (sST2) isoforms 18.…”

Regulation of Langerhans cell functions in a hypoxic environment

“…IL-33 is an Balarmin^and releases upon cell injury [39,40], whereas ST2 has two isoforms, the full-length transmembrane ST2 and the truncated soluble sST2 [41]. The interaction of IL-33 with ST2 activates ILC2, memory Th2, and mast cells, which secrete IL-5 and IL-13 and facilitate pulmonary eosinophilic inflammation [26,42].…”