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.
Highlights
In 1989, the Il1rl1 gene product, which has been given the alias ST2 and defined as the IL-33 receptor, as it binds to IL-33, was discovered [1, 2]
ST2/IL-33 signaling in Tregs was first suggested to enhance their protective ability in an experimental colitis model in which IL-33 treatment ameliorated colonic tissue injury and colitis symptoms [41]
ST2/IL-33 signaling in Tregs has been shown to increase Treg frequency and decrease IL-17 and IFN-γ productions in an experimental autoimmune encephalomyelitis (EAE) model [102, 103]
Summary
In 1989, the Il1rl gene product, which has been given the alias ST2 and defined as the IL-33 receptor, as it binds to IL-33, was discovered [1, 2]. In a non-canonical MyD88-dependent pathway [59], IFN regulatory factor (IRF) 1 signaling can inhibit Tregs by binding to the Foxp promoter and preventing Foxp transcription in murine T cells [60]; this signaling leading to IRF1 activation through MyD88 has only been shown to be induced using CpG-B, a TLR9 agonist and a pathway independent from ST2/IL-33 [59]. IL-33 polarization of antigen-stimulated murine and human naïve CD4+ T cells leads to high IL-5 production but no IL-4 production, independent of GATA3 and STAT6 induction but dependent on MAPK and NF-κB signaling [88, 89] Adoptive transfer of these cells into naïve IL-4−/− mice still triggered airway inflammation [88]. In a model of GVHD, treatment of mice daily with IL-33 from 10 days pretransplantation to day 4 posttransplantation enhanced the frequency of ST2+ Tregs, which persisted after irradiation, leading to disease amelioration through prevention of T conventional cell accumulation in target GVHD
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