Mast cells control lung type 2 inflammation via prostaglandin E(2)-driven soluble ST2.

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 E(2) (PGE(2)) drives production of sST2 to limit features of lung T2I. PGE(2)-deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE(2) metabolites correlate with serum sST2. In mice, PGE(2) 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 PGE(2) or ST2 expression by MCs back to control levels. PGE(2) deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE(2) thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE(2) states.