The orphan G protein–coupled receptor 141 expressed in myeloid cells functions as an inflammation suppressor

Abstract

Abstract G protein–coupled receptors (GPCRs) regulate many cellular processes in response to various stimuli, including light, hormones, neurotransmitters, and odorants, some of which play critical roles in innate and adaptive immune responses. However, the physiological functions of many GPCRs and the involvement of them in autoimmune diseases of the central nervous system remain unclear. Here, we demonstrate that GPR141, an orphan GPCR belonging to the class A receptor family, suppresses immune responses. High GPR141 messenger RNA levels were expressed in myeloid-lineage cells, including neutrophils (CD11b + Gr1+), monocytes (CD11b + Gr1−Ly6C+ and CD11b + Gr1−Ly6C−), macrophages (F4/80+), and dendritic cells (CD11c+). Gpr141  −/− mice, which we independently generated, displayed almost no abnormalities in myeloid cell differentiation and compartmentalization in the spleen and bone marrow under steady-state conditions. However, Gpr141 deficiency exacerbated disease conditions of experimental autoimmune encephalomyelitis, an autoimmune disease model for multiple sclerosis, with increased inflammation in the spinal cord. Gpr141  −/− mice showed increased CD11b + Gr1+ neutrophils, CD11b + Gr1− monocytes, CD11c+ dendritic cells, and CD4+ T cell infiltration into the experimental autoimmune encephalomyelitis–induced spinal cord compared with littermate control mice. Lymphocytes enriched from Gpr141  −/− mice immunized with myelin oligodendrocyte glycoprotein 35–55 produced high amounts of interferon-γ, interleukin-17A, and interleukin-6 compared with those from wild-type mice. Moreover, CD11c+ dendritic cells (DCs) purified from Gpr141  −/− mice increased cytokine production of myelin oligodendrocyte glycoprotein 35–55–specific T cells. These findings suggest that GPR141 functions as a negative regulator of immune responses by controlling the functions of monocytes and dendritic cells and that targeting GPR141 may be a possible therapeutic intervention for modulating chronic inflammatory diseases.