GPR171 restrains intestinal inflammation by suppressing FABP5-mediated Th17 cell differentiation and lipid metabolism.

Abstract

GPR171 suppresses T cell immune responses involved in antitumour immunity, while its role in inflammatory bowel disease (IBD) pathogenesis remains unclear. We aimed to investigate the role of GPR171 in modulating CD4⁺ T cell effector functions in IBD and evaluate its therapeutic potential. We analysed GPR171 expression in colon biopsies and peripheral blood samples from patients with IBD and assessed the impact of GPR171 on CD4⁺ T cell differentiation through administration of its endogenous ligand (BigLEN). We further determined the role of GPR171 in dextran sulfate sodium (DSS)-induced colitis and CD45RB^highCD4⁺ T-cell transfer colitis model and deciphered the underlying mechanisms using RNA sequencing (RNA-seq) and lipidomics. We developed a novel BigLEN-based Fc fusion protein (BigLEN-Fc) and evaluated its potential in preventing and treating colitis. GPR171 was markedly increased in inflamed mucosa and CD4⁺ T cells of patients with IBD compared with controls. BigLEN-triggered GPR171 activation inhibited Th17 cell differentiation in vitro. GPR171 deficiency exacerbated DSS- and CD45RB^highCD4⁺ T cell-induced colitis in mice, characterised by increased Th17 cell responses in intestinal mucosa. Mechanistically, GPR171 deficiency promoted Th17 cell differentiation and altered lipidome profile in Th17 cells via the cAMP-pCREB-FABP5 axis. Blockage of FABP5 reduced Th17 cell differentiation in vitro and ameliorated DSS-induced colitis in <i>Gpr171</i> ^-/- mice. Furthermore, BigLEN-mutFc administration potently mitigated colitis in mice. GPR171 deficiency promotes Th17 cell differentiation and causes lipid metabolism perturbation, contributing to intestinal inflammation in a FABP5-dependent manner. Target therapy (eg, BigLEN-Fc) represents a novel therapeutic approach for IBD treatment.