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

Area of Science:

• Immunology
• Endocrinology
• Molecular Biology

Background:

• Type 1 diabetes (T1D) involves immune-mediated destruction of pancreatic beta cells.
• Inflammatory pathways, including the 12-lipoxygenase (12-LOX) pathway producing 12-HETE, exacerbate beta cell dysfunction and apoptosis.
• G protein-coupled receptor 31 (GPR31) is a potential receptor for 12-HETE.

Purpose of the Study:

• To investigate the role of GPR31 in beta cell and macrophage inflammatory responses in the context of T1D.
• To determine if targeting GPR31 can ameliorate T1D-associated pathology.

Main Methods:

• Generation of GPR31 knockout (KO) mice.
• Treatment of wildtype and GPR31 KO islets with pro-inflammatory cytokines followed by RNA sequencing.
• Assessment of macrophage migration and inflammatory signaling in GPR31 KO macrophages.
• Induction of diabetes using streptozotocin in wildtype and GPR31 KO mice.
• siRNA knockdown of GPR31 in non-obese diabetic (NOD) mice.

Main Results:

• GPR31 deficiency in islets reduced inflammation and oxidative stress.
• GPR31 KO macrophages exhibited reduced migration and inflammatory signaling.
• GPR31 KO mice showed improved glucose tolerance and preserved beta cell mass after streptozotocin treatment.
• GPR31 knockdown in NOD mice decreased insulitis, macrophage infiltration, and oxidative stress.

Conclusions:

• GPR31 mediates pro-inflammatory responses to 12-HETE in both beta cells and macrophages.
• GPR31 plays a significant role in T1D pathogenesis.
• Targeting GPR31 represents a potential therapeutic strategy for T1D.