NLRC5 regulates TGF-β1-induced proliferation and activation of hepatic stellate cells during hepatic fibrosis.

Therapeutic management of liver fibrosis remains an unsolved clinical problem. Hepatic accumulation of extracellular matrix, mainly collagen, is mediated by the production of transforming growth factor-β1 (TGF-β1) in hepatic stellate cells (HSCs). NLRC5, the largest member of the NLR protein family, has recently been identified as a critical regulator of immune responses. Novel evidence shows that NLRC5 is an important negative modulator of inflammatory pathways. Herein, we determined the regulation of NLRC5 in liver fibrogenesis and its underlying mechanisms. We have shown that NLRC5 was upregulated in human liver fibrotic tissues. Overexpression of NLRC5 resulted in an upregulation of collagen 1 and α-smooth muscle actin expression in HSC LX-2 cells, which was inhibited by NLRC5 knockdown with its siRNA. Furthermore, NLRC5 deficiency significantly suppressed TGF-β1-induced proliferation but increased apoptosis (i.e., increased caspases-3, DR4 and DR5) in LX-2 cells. In addition, knockdown of NLRC5 promoted the activation of NF-κB signaling pathways but abrogated phosphorylation of Smad2 and Smad3 proteins in response to TGF-β1. These results indicate that NLRC5 is a potent pro-fibrogenic molecule for HSC activation through TGF-β1/Smad and NF-κB signaling pathways. NLRC5 inhibition would be a promising therapeutic avenue for treating hepatic fibrosis.