GPR17 Regulates Immune Pulmonary Inflammation Induced by House Dust Mites

Abstract

Antagonists of the type 1 cysteinyl leukotriene receptor (CysLT1R) are efficacious for bronchoconstriction in humans with bronchial asthma; however, the clinical response to these drugs is heterogeneous. In particular, how CysLT1R expression and function are constitutively regulated in vivo is not known. In this study, we show that a seven-transmembrane receptor, GPR17, negatively regulates the CysLT1R-mediated inflammatory cell accumulation in the bronchoalveolar lavage fluid and lung, the levels of IgE and specific IgG1 in serum, and Th2/Th17 cytokine expression in the lung after intranasal sensitization and challenge with the house dust mite (extract of Dermatophagoides farinae [Df]) in mice. Sensitization of naive wild-type recipients with Df-pulsed bone marrow-derived dendritic cells of each genotype or sensitization of each genotype with Df-pulsed wild-type bone marrow-derived dendritic cells and Df challenge revealed markedly increased pulmonary inflammatory and serum IgE responses for GPR17-deficient mice as compared with wild-type mice and reduced responses in the genotypes lacking CysLT1R. These findings reveal a constitutive negative regulation of CysLT1R functions by GPR17 in both the Ag presentation and downstream phases of allergic pulmonary inflammation.