The G Protein-Coupled Receptor GPR31 Promotes Pro-inflammatory Responses in Pancreatic Islets and Macrophages

In type 1 diabetes (T1D), the innate and adaptive immune systems attack and eventually destroy the insulin-secreting pancreatic β cells. During this process, β cells activate inflammatory signaling pathways that augment the dysfunction and destruction imposed by cellular autoimmunity. The 12-lipoxygenase (12-LOX) pathway produces the pro-inflammatory eicosanoid 12-HETE, which induces oxidative and endoplasmic reticulum stress and results in diminished insulin secretion and apoptosis. The G protein-coupled receptor GPR31 has been identified as a putative receptor for 12-HETE. In this study, we generated conventional GPR31 knockout (KO) mice on the C57BL/6J background. To interrogate the role of GPR31 in β cells, we treated islets from wildtype and Gpr31b-/- mice with pro-inflammatory cytokines and subjected the islets to RNA sequencing. Differentially expressed pathways in Gpr31b-/- islets included those pertaining to inflammation and oxidative stress, consistent with functional studies that demonstrated reduced cytokine-induced oxidative stress in Gpr31b-/- islets compared to wildtype controls. Bone marrow-derived macrophages from Gpr31b-/- mice showed reduced macrophage migration and decreased inflammatory IFN-α and IFN-γ signaling by RNA sequencing. To mimic islet and macrophage inflammation as seen in T1D, wildtype and Gpr31b-/- mice were treated with the diabetogenic toxin streptozotocin. Compared to wildtype, Gpr31b-/- mice had improved glucose tolerance and preserved β-cell mass. siRNA knockdown of Gpr31b in non-obese diabetic (NOD) mice reduced insulitis, macrophage infiltration, and oxidative stress. Collectively, these findings are consistent with previously published data using 12-LOX KO mice and suggest that GPR31 mediates the pro-inflammatory responses of 12-HETE in both β cells and macrophages.