Resolvin D5 Inhibits CXCL8 Expression in Colonic Epithelial Cells Through Activating GPR101 to Impede Neutrophil Recruitment and Consequently Alleviate Ulcerative Colitis

In the colonic mucosal tissues of patients with ulcerative colitis (UC), the levels of resolvin D5 (RvD5), a specialized pro-resolving mediator, are significantly reduced and negatively correlate with disease severity. Whether RvD5 can ameliorate UC remain unclear. Here, we show that exogenous supplement of RvD5 remarkably reduces neutrophil infiltration within the colonic mucosal epithelial layers and alleviates dextran sulfate sodium-induced colitis in mice. Adoptive transfer of neutrophils significantly attenuates the alleviation of RvD5 against colitis, indicating that inhibition of neutrophil infiltration plays a crucial role in the anti-colitis effect. Mechanistically, RvD5 activates GPR101 in colonic epithelial cells to selectively downregulate CXCL8 expression through inhibiting pSTAT1 expression and thereby suppressing neutrophil infiltration within colonic mucosal epithelial layer, and GPR101 knockdown attenuates the above-mentioned effect of RvD5. Based on molecular docking screening from natural product library, epimedin A1 is identified as a novel enhancer of RvD5 biosynthesis in M2 macrophages, which functions through allosteric inhibition of 5-lipoxygenase (5-LOX). Epimedin A1 significantly elevates RvD5 levels in colonic tissue, suppresses CXCL8 expression in colonic epithelial cells, and reduces mucosal epithelial neutrophil infiltration in colitis mice. In summary, RvD5 and its biosynthesis promoter epimedin A1 are promising as therapeutic agents of UC.