Role of NLRC5 in progression and reversal of hepatic fibrosis

• Published in: Toxicology and applied pharmacology 2016-03, Vol.294, p.43-53
• Main Authors: Liu, Xuejiao, Wu, Yuting, Yang, Yang, Li, Wanxia, Huang, Cheng, Meng, Xiaoming, Li, Jun
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Actins - genetics; ANIMAL TISSUES; Animals; CARBON; CARBON TETRACHLORIDE; Carbon Tetrachloride Poisoning - genetics; Carbon Tetrachloride Poisoning - pathology; Collagen Type I - genetics; FIBROSIS; Gene Knockdown Techniques; Hepatic fibrosis; Hepatic Stellate Cells - metabolism; HSCs reversion; I-kappa B Proteins - metabolism; IN VITRO; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - biosynthesis; Intracellular Signaling Peptides and Proteins - genetics; LIVER; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; MICE; Mice, Inbred C57BL; NLRC5; Phosphorylation; PLANT TISSUES; POLYMERASE CHAIN REACTION; Reversal of hepatic fibrosis; RNA, Small Interfering - genetics; Transcription Factor RelA - metabolism; Transfection; Transforming Growth Factor beta - pharmacology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2016.01.012

NLRC5, as the largest member of NLRs family, has recently been identified as a critical regulator of immune responses through negatively regulating NF-κB which is associated with the development of hepatic fibrosis. However, the expression and potential roles of NLRC5 in hepatic fibrosis and its reversal are still to be defined. C57BL/6 mice were treatment with carbon tetrachloride (CCl4) induce hepatic fibrosis and its reversal. In vitro, models of hepatic fibrosis and its reversal are established by the treatment with TGF-β and MDI. The expression of NLRC5 was determined by RT-PCR, Western blot and immunohistochemistry. Consequently, NLRC5 was overexpressed or knockdown by transfecting PEGFP-C2-NLRC5 or NLRC5-siRNA respectively in the reversal of hepatic fibrosis, and the expression of fibrogenic genes such as α-SMA and Col1α1 was quantified. The NF-κB activity was detected as well. Immunohistochemistry, RT-PCR and Western blot analysis with liver tissues and primary HSCs showed that NLRC5 was highly expressed in hepatic fibrosis and correspondingly decreased in the reversal stage. The differential expression of NLRC5 was confirmed in vitro. Enforced NLRC5 expression increased the expression of α-SMA and Col1α1, and blockade of NLRC5 reduced the fibrotic response. While the opposite expression of phosphorylated NF-кB p65 and phospho-IκBα was found. NLRC5 is differentially expressed in hepatic tissues and hepatic stellate cells during hepatic fibrosis and its reversal. All the data indicated that NLRC5 may play a crucial role in regulating the reversal of hepatic fibrosis through NF-κB signaling pathway. [Display omitted] •The activated HSCs can be reverted to quiescent HSCs by MDI treatment.•NLRC5 expressed differentially during different stages of hepatic fibrosis and its reversal.•Enforced NLRC5 in reverted LX-c cells boosted the expression of α-SMA and Col1α1.•Blockade of NLRC5 diminished α-SMA and Col1α1 expression.•NLRC5 might provide a novel therapeutic approach for liver fibrosis.