Mast cells control lung type 2 inflammation via prostaglandin E2-driven soluble ST2, 2024, Kinan Alhallak et al

Highlights

• PGE2 is necessary to elevate sST2 levels in the lung with type 2 lung inflammation
• Intraepithelial mast cells are the principal source of PGE2-driven lung sST2 production
• Deficiency of mast-cell-derived sST2 exaggerates type 2 lung inflammation
• PGE2 alters the mast cell transcriptome and promotes short Il1rl1 expression

Summary
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.

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NIAID-funded scientists discovered that immune cells called mast cells may protect from allergic disease by reducing allergic inflammation in mice – a surprising finding given that mast cells are primarily believed to cause allergic reactions