Adiponectin deficiency prevents chronic colitis-associated colonic fibrosis via inhibiting CXCL13 production

Colonic fibrosis is a long-term complication of inflammatory bowel disease (IBD), often leading to functional impairment, intestinal obstruction, and surgery. Adiponectin (APN) is an adipokine derived from adipocytes that plays a pleiotropic role in fibrosis regulation, depending on tissue and cell type specific or disease context, but its role in colonic fibrosis remains unclear.

To explore the role and involved mechanism of APN in chronic colitis-associated colonic fibrosis.

Studies were performed in GEO database, colonic tissues of UC patients, dextran sulfate sodium (DSS)-induced colonic fibrosis in male wild-type (WT) and APN^-/- mice, mouse L929 and human CCD-18Co fibroblasts treated with recombinant CXCL13 protein, and colonic fibrosis in WT mice infected with shRNA of CXCL13.

APN was highly expressed in the colonic tissues of UC patients and positively correlated with the colonoscopy score and colonic fibrosis markers COL1A1 and COL3A1. APN deficiency significantly improved chronic colitis-induced colonic fibrosis in mice with down-regulating collagenase accumulation and expressions of TGF-β, α-SMA, COL1A1, COL3A1, and MMP-9 in colonic tissues. Transcriptomics showed that APN deficiency mainly affected cytokine-cytokine receptor interactions, especially CXCL13 signaling. Follow-up studies showed that APN deficiency significantly decreased the number of colonic F4/80⁺CD206⁺CXCL13⁺ macrophages by weakening Akt phosphorylation. Additional experiments confirmed that CXCL13 notably increased the expressions of α-SMA and COL1A1 in mouse and human fibroblasts by activating p-Akt, p-p38, p-ERK, and p-JNK. Moreover, inhibiting CXCL13 with shRNA significantly ameliorated colonic fibrosis in mice with DSS-induced chronic colitis. Immunohistochemistry analysis revealed high expression of CXCL13 in the colon tissues of patients with UC, showing a positive correlation with APN, COL1A1, and COL3A1.

APN contributes to the progression of colonic fibrosis and can exacerbate this condition by regulating the secretion of CXCL13 in the colon, offering potential new perspectives on the pathophysiology of colonic fibrosis.