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

ABSTRACT: In type 1 diabetes (T1D), the innate and adaptive immune systems attack and eventually destroy the insulin-secreting islet 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 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 β 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 β-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 β cell.

ORGANISM(S): Mus musculus

PROVIDER: GSE285039 | GEO | 2025/01/06

REPOSITORIES: GEO

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Inhibition of 12/15-Lipoxygenase Protects Against β Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

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