CXCL13 suppresses liver regeneration through the negative regulation of HGF signaling

Abstract

Abstract Insufficient liver regeneration increases the risk of postoperative liver failure following liver transplantation or partial hepatectomy (PHx). Numerous growth factors and cytokines are related to liver regeneration; however, the underlying mechanisms have not been fully elucidated. In this study, CXCL13 was identified as a key factor delaying liver regeneration after PHx. We observed that CXCL13 expression was upregulated in PHx mice and patients following liver resection. CXCL13 deficiency accelerated liver regeneration, whereas these effects were abolished by recombinant murine CXCL13 administration. Moreover, proteomics analyses indicated that HGF levels in the serum after PHx were significantly greater in Cxcl13 −/− mice than in WT mice. Further analysis revealed that CXCL13 deficiency promoted liver regeneration via elevated HGF expression in reparative macrophages and subsequent activated the HGF/c-MET axis in hepatocytes. Additionally, deficiency of macrophage CXCR5, the receptor for CXCL13, augmented liver regeneration and elevated HGF expression after PHx. Mechanistically, CXCL13 inhibited HGF expression in reparative macrophages via CXCR5-mediated AKT/FoxO3a signaling. We further determined that noncanonical NF-κB signaling activation induced CXCL13 expression in hepatic macrophages. Importantly, treatment with CXCL13-neutralizing antibody effectively improved liver regeneration in mice PHx model. Overall, our findings revealed a novel function of CXCL13 in negatively regulating liver regeneration. The underlying mechanism involved CXCL13/CXCR5-mediated FoxO3a signaling, which downregulated HGF expression in reparative macrophages and subsequently attenuated hepatocyte proliferation through inactivating HGF/c-MET signaling. These data suggest that therapeutic targeting of the CXCL13 signaling axis might decrease the risk of postoperative liver failure.