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

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 islets, primary islets were isolated from Gpr31b knockout and wildtype mice. Islets were treated with and without proinflammatory cytokines (TNF-a, IFN-?, IL-1ß) for 24 hours. RNA was isolated and processed for RNA-sequencing.