Targeting GPR183 to reduce peripheral sensitization: evidence from rodent and human tissue analyses

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Abstract Peripheral sensitization is a key process in the development of painful inflammatory conditions, driven in part by immune-cell mediator release following tissue injury. The G protein–coupled receptor, GPR183, predominantly expressed on immune cells, regulates their migration, positioning, and mediator production. Yet its role in peripheral sensitization and the specific immune cells involved remains insufficiently understood. In rats, intraplantar injection of 7α,25-dihydroxycholesterol (7α,25-OHC), the most potent endogenous GPR183 ligand, produced long-lasting nociception that was prevented by the selective GPR183 antagonist SAE-14. Because GPR183 activates ERK signaling, which influences pain pathways including nitric oxide synthase (NOS) activity and NO formation, we used NOS inhibitors and knockout animals to test the contribution of inducible and neuronal NOS isoforms to 7α,25-OHC-induced sensitization. We found that both isoforms influence this response, independent of cyclooxygenases. In a well-characterized rat incisional injury model, GPR183 protein expression increased in injured paw tissue, and SAE-14 reversed hypersensitivity. Meta-analysis of human post-surgical skin samples similarly showed elevated GPR183 expression and transcriptional changes favoring 7α,25-OHC production after injury. We identified macrophages and Langerhans cells (LCs) as the principal GPR183-expressing cell types in human skin. LC ablation studies revealed that 7α,25-OHC-evoked hypersensitivity does not depend on LCs, implicating GPR183 + macrophages as predominant drivers of GPR3-induced hypersensitivity. Overall, our findings define the cellular and molecular pathways linking GPR183 to peripheral sensitization and highlight GPR183 antagonism as a promising strategy for pain management.

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