The G Protein-Coupled Receptor GPR31 Promotes Proinflammatory Responses in Pancreatic Islets and Macrophages II

In type 1 diabetes (T1D), the innate and adaptive immune systems attack and eventually destroy the insulin-secreting islet ß cells. During this process, ß 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 31 (GPR31) has been identified as a putative receptor for 12-HETE. In this study, we generated conventional GPR31 knockout mice. To interrogate the role of GPR31 in ß cells, we treated islets from wildtype and Gpr31b-/- mice with proinflammatory cytokines and subjected the islets to RNA sequencing. Differentially expressed genes in Gpr31b-/- islets included those pertaining to receptor signaling, inflammation, oxidative stress, and macrophage migration — effects that are reminiscent of 12-LOX inhibition. Bone-marrow derived macrophages from Gpr31b-/- mice had reduced macrophage migration compared to wildtype macrophages. To mimic islet and macrophage inflammation as seen in T1D, wildtype and Gpr31b-/- mice were treated with the pro-diabetic toxin streptozotocin. Compared to wildtype, Gpr31b-/- mice had improved glucose tolerance and preserved ß-cell mass. These results are consistent with previously published data using 12-LOX knockout mice and suggests that GPR31 mediates the proinflammatory responses of 12-HETE in the ß cell. Overall design: To investigate the knockout of Gpr31b in macrophages, bone marrow bone marrow was harvested from WT and Gpr31b KO mice and bone marrow devired macrophages were isolated to M0 macrophages. M0 macrophages were stimulated to M1 macrophages with LPS and IFN-?. RNA was isolated and processed for RNA-sequencing.