Mast cell-specific CysLT2 receptor signaling inhibits cysteinyl leukotriene-dependent mast cell activation and type 2 allergic lung inflammation.

Cysteinyl leukotrienes (cysLTs) promote type 2 inflammation (T2I) by signaling through the type 1 and 3 cysLT-specific G protein-coupled receptors (GPCRs) (CysLT(1)R and CysLT(3)R). The type 2 cysteinyl leukotriene receptor (CysLT(2)R) can either promote or protect from T2I in vivo. The anti-inflammatory effects of CysLT(2)R are poorly understood. We find that prolonged CysLT(2)R signaling induces adenylate cyclase (AC) potentiation and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation that inhibits CysLT(1)R-driven mast cell (MC) activation. CysLT(2)R potentiates cAMP/PKA activation through classical Gs-linked GPCRs even in the absence of their ligands through a mechanism that requires Gβγ proteins. An asthma-associated CysLT(2)R mutant displays loss of LTD(4)-induced AC potentiation and PKA activation. Deletion of MC-intrinsic CysLT(2)R amplifies dust mite-induced lung T2I that is CysLT(1)R dependent. CysLT(2)R is a checkpoint molecule using delayed Gβγ-mediated cAMP potentiation. Biased agonists that selectively harness this property have therapeutic potential in asthma and other T2I-linked diseases.