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.