CXCL5 is associated with neutrophil-driven intestinal inflammation and IL-17-associated epithelial signaling in inflammatory bowel disease.

CXCL5 is an epithelial cell-derived neutrophil-activating peptide implicated in intestinal inflammation. We investigated the role of CXCL5 in inflammatory bowel disease (IBD), with a focus on its interaction with IL-17 signaling. CXCL5 expression in colonic tissues from patients with IBD and its association with clinical disease activity were analyzed. Publicly available single-cell RNA sequencing data were examined to identify CXCL5-expressing cell populations. Acute and chronic murine colitis models were used to assess the functional role of CXCL5 in vivo, and cytokine expression was evaluated. In vitro experiments were performed in human intestinal epithelial cells to examine CXCL5 regulation by inflammatory cytokines. CXCL5 expression positively correlated with fecal calprotectin levels in IBD patients and was significantly reduced in ulcerative colitis patients achieving endoscopic mucosal healing. Single-cell analysis revealed CXCL5 expression concentrated in a discrete epithelial cluster. IL17RA was broadly expressed across epithelial and immune cell populations, including the CXCL5-expressing epithelial subset, which may suggest the capacity of these cells to respond to IL-17A signaling. In acute DSS-induced colitis, CXCL5 deficiency markedly attenuated inflammation and neutrophil recruitment, accompanied by reduced IL-17A expression. Conversely, CXCL5 deficiency did not significantly alter disease severity in chronic colitis models. In vitro, TNF-α induced CXCL5 expression, which was further enhanced by IL-17A. CXCL5 contributes to neutrophil-driven intestinal inflammation in a phase-dependent manner and the CXCL5/IL-17 axis may represent a potential therapeutic target, warranting further mechanistic investigation.