The Important Roles of Natural Killer Cells in Liver Fibrosis

Abstract

Liver fibrosis accompanies the development of various chronic liver diseases and promotes their progression. It is characterized by the abnormal accumulation of extracellular matrix proteins (ECM) and impaired ECM degradation. Activated hepatic stellate cells (HSCs) are the major cellular source of ECM-producing myofibroblasts. If liver fibrosis is uncontrolled, it may lead to cirrhosis and even liver cancer, primarily hepatocellular carcinoma (HCC). Natural killer (NK) cells are a key component of innate immunity and have miscellaneous roles in liver health and disease. Accumulating evidence shows that NK cells play dual roles in the development and progression of liver fibrosis, including profibrotic and anti-fibrotic functions. Regulating NK cells can suppress the activation of HSCs and improve their cytotoxicity against activated HSCs or myofibroblasts to reverse liver fibrosis. Cells such as regulatory T cells (Tregs) and molecules such as prostaglandin E receptor 3 (EP3) can regulate the cytotoxic function of NK cells. In addition, treatments such as alcohol dehydrogenase 3 (ADH3) inhibitors, microRNAs, natural killer group 2, member D (NKG2D) activators, and natural products can enhance NK cell function to inhibit liver fibrosis. In this review, we summarized the cellular and molecular factors that affect the interaction of NK cells with HSCs, as well as the treatments that regulate NK cell function against liver fibrosis. Despite a lot of information about NK cells and their interaction with HSCs, our current knowledge is still insufficient to explain the complex crosstalk between these cells and hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, B cells, and T cells, as well as thrombocytes, regarding the development and progression of liver fibrosis.

Biomarkers of Innate Immunity and Immunological Susceptibility to Viral Infection in Patients with Alcoholic Cirrhosis

“…KIR receptors on the NK cell and their specific ligands, HLA class I (MHC-1) molecules, also play an essential role in the antifibrotic effect [45]. Inhibitory KIR receptors (iKIR) present on the NK cell bind to their ligands, HLA class I (MHC-1) molecules present on the hepatic stellate cell (HSC), inhibiting its destruction.…”

Is the Development of Ascites in Alcoholic Liver Patients Influenced by Specific KIR/HLA Gene Profiles?

“…Furthermore, we only studied the KIR and HLA genes. Beyond the KIR and HLA genes, analysis of SNPs in genes for alcohol metabolism and immune function (e.g., PNPLA3, TM6SF2) [61][62][63][64][65], expression of liver fibrosis microRNAs (miR-122, miR-34a) [66][67][68], and epigenetic methylation patterns and genetic polymorphisms affecting oxidative stress [69,70] could provide further insight into alcoholic cirrhosis and ascites. In addition, examination of inflammation-regulating cytokine gene variants, a broader range of HLA alleles, and expanded KIR haplotypes, with integration of multiomic data on proteomic, metabolomic, and transcriptomic biomarkers, could significantly improve comprehensive identification of relevant genetic factors that influence pathogenesis.…”