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) (CysLT1R and CysLT3R). The type 2 cysteinyl leukotriene receptor (CysLT2R) can either promote or protect from T2I in vivo. The anti-inflammatory effects of CysLT2R are poorly understood. We find that prolonged CysLT2R signaling induces adenylate cyclase (AC) potentiation and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation that inhibits CysLT1R-driven mast cell (MC) activation. CysLT2R 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 CysLT2R mutant displays loss of LTD4-induced AC potentiation and PKA activation. Deletion of MC-intrinsic CysLT2R amplifies dust mite-induced lung T2I that is CysLT1R dependent. CysLT2R 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.