GPR183-mediated immune cell positioning and function: an integrative perspective across ligand gradients, tissue environments, and disease stages

Abstract

G protein-coupled receptor 183 (GPR183), also known as EBI2, is a chemoattractant receptor whose principal endogenous ligand is 7α,25-dihydroxycholesterol (7α,25-OHC). Its expression varies dynamically across immune-cell subsets and activation states. By sensing local 7α,25-OHC gradients, GPR183 converts tissue metabolic cues into spatial information, thereby regulating immune-cell migration, tissue distribution, and function. Dynamic receptor expression, ligand synthesis and degradation, responding cell type, and the tissue microenvironment collectively shape the direction of pathway activity, whereas intervention studies in animals and longitudinal observations establish disease stage as a temporal coordinate for interpreting divergent effects. Genetic, pharmacological, and cell-engineering studies provide functional evidence that GPR183 contributes to lymphoid-tissue compartmentalization, host defense, inflammatory responses, tissue repair, and tumor-immune remodeling. Analyses of patient tissues and clinical cohorts extend this mechanistic framework to associations with disease activity, treatment response, and prognosis. Three intervention strategies have emerged: receptor agonism, pharmacological inhibition, and immune-cell engineering. The oral antagonist IPG11406 has entered early clinical evaluation, whereas preclinical assessment of other candidate strategies has focused on ligand stability, tissue selectivity, and long-term immune safety. This review integrates current evidence across four dimensions - immune-cell type, the 7α,25-OHC gradient, tissue microenvironment, and disease stage - and organizes the disease-related actions of GPR183 and potential stratified interventions around pathogenic recruitment, protective recruitment, tissue repair, tumor-immune remodeling, and biomarker applications.