ST2,
also known as IL-1 R4 and T1, is an Interleukin-1 receptor family glycoprotein
that contributes to Th2 immune responses. Human ST2 consists of a 310 amino
acid extracellular domain (ECD) with three Ig-like domains, a 21 aa
transmembrane segment, and a 207 aa cytoplasmic domain with an intracellular
TIR domain. ST2 is expressed on the surface of mast cells, activated Th2 cells,
macrophages, and cardiac myocytes. It binds IL-33, a cytokine that is
upregulated by inflammation or mechanical strain in smooth muscle cells, airway
epithelia, keratinocytes, and cardiac fibroblasts. IL-33 binding induces the
association of ST2 with IL-1R AcP, a shared signaling subunit that also
associates with IL-1 RI and IL-1 R rp2. In macrophages, ST2 interferes with
signaling from IL-1 RI and TLR4 by sequestering the adaptor proteins MyD88 and
Mal. In addition to its role in promoting mast cell and Th2 dependent
inflammation, ST2 activation enhances antigen induced hypernociception and
protects from atherosclerosis and cardiac hypertrophy. Upon tissue injury,
induces UCP2-dependent mitochondrial rewiring that attenuates the generation of
reactive oxygen species and preserves the integrity of Krebs cycle required for
persistent production of itaconate and subsequent GATA3-dependent
differentiation of inflammation-resolving alternatively activated macrophages.
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