Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2

Abstract

Severe asthma and sinus disease are consequences of type 2 inflammation (T2I), mediated by interleukin (IL)-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E₂ (PGE₂) drives production of sST2 to limit features of lung T2I. PGE₂-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE₂ metabolites correlate with serum sST2. In mice, PGE₂ enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs, or E prostanoid (EP)₂ receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE₂ or ST2 expression by MCs back to control levels. PGE₂ deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE₂ thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE₂ states.