CXCL16/CXCR6 axis promotes bleomycin-induced fibrotic process in MRC-5 cells via the PI3K/AKT/FOXO3a pathway

Abstract Objective Interstitial lung disease (ILD) is a progressive and irreversible lung disease with very limited therapeutic options. Previous studies have found that chemokine ligands CXCL16 and CXCR6 play critical roles in organ fibrosis. However, whether CXCL16 and CXCR6 are also involved in the pathogenesis of ILD, as well as their regulatory role in pulmonary fibrosis, has not been reported. Methods In this study, we detected CXCL16 levels in patients with rheumatoid arthritis-associated ILD (RA-ILD) and examined the critical role of the CXCL16/CXCR6 axis in the proliferation and collagen production of human pulmonary fibroblasts (MRC-5 cells). The effect of anti-CXCL16 antibody on the bleomycin-induced fibrogenesis in cultured MRC-5 cells was also evaluated. Results Our results indicated that serum soluble CXCL16 was significantly higher in RA-ILD patients and also associated with the severity of lung fibrosis. CXCL16 facilitates fibrosis by enhancing proliferation, migration, and collagen production of MRC-5 cells. Furthermore, a synergistic fibrogenic effect of CXCL16 and bleomycin has been found. CXCL16 stimulated the activation of PI3K/AKT/FOXO3a signaling pathway in MRC-5 cells, and the inhibition by specific inhibitors Wortmannin and LY294002, or knockdown of CXCR6 by siRNA also suppressed the biological functions of MRC-5 cells mediated by CXCL16. Similarly, down-regulation of CXCR6 also partly blocked BLM-induced fibrogenesis in MRC-5 cells. Conclusions CXCL16/CXCR6 axis promotes proliferation and collagen production of MRC-5 cells by the PI3K/AKT/FOXO3a signaling pathway, and inhibition of the CXCL16/CXCR6 axis may provide a new therapeutic strategy targeting pulmonary fibrosis.