Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells

Abstract

Background and Aims The important roles of glutamate and metabotropic glutamate receptor 5 (mGluR5) in HSCs have recently been reported in various liver diseases; however, the mechanism linking the glutamine/glutamate metabolism and mGluR5 in liver fibrosis remains unclear. Here, we report that mGluR5 activation in natural killer (NK) cells attenuates liver fibrosis through increased cytotoxicity and interferon‐γ (IFN‐γ) production in both mice and humans. Approach and Results Following 2‐week injection of carbon tetrachloride (CCl4) or 5‐week methionine‐deficient and choline‐deficient diet, liver fibrosis was more aggravated in mGluR5 knockout mice with significantly decreased frequency of NK cells compared with wild‐type mice. Consistently, NK cell–specific mGluR5 knockout mice had aggravated CCl4‐induced liver fibrosis with decreased production of IFN‐γ. Conversely, in vitro activation of mGluR5 in NK cells significantly increased the expression of anti‐fibrosis‐related genes including Ifng, Prf1 (perforin), and Klrk1 (killer cell lectin like receptor K1) and the production of IFN‐γ through the mitogen‐activated extracellular signal‐regulated kinase/extracellular signal‐related kinase pathway, contributing to the increased cytotoxicity against activated HSCs. However, we found that the uptake of glutamate was increased in activated HSCs, resulting in shortage of extracellular glutamate and reduced stimulation of mGluR5 in NK cells. Consequently, this could enable HSCs to evade NK cell cytotoxicity in advanced liver fibrosis. In vivo, pharmacologic activation of mGluR5 accelerated CCl4‐induced liver fibrosis regression by restoring NK cell cytotoxicity. In humans, mGluR5 activation enhanced the cytotoxicity of NK cells isolated from healthy donors, but not from patients with cirrhosis with significantly reduced mGluR5 expression in NK cells. Conclusions mGluR5 plays important roles in attenuating liver fibrosis by augmenting NK cell cytotoxicity, which could be used as a potential therapeutic target for liver fibrosis.

Identification of Immune Microenvironment Changes and the Expression of Immune-Related Genes in Liver Cirrhosis

“…IFN-γ not only inhibits HSC activation and ECM synthesis directly ( 20 ) but also amplifies NK-cell cytotoxicity against HSCs by promoting NKG2D expression on liver NK cells to attenuate liver fibrosis ( 21 ). A decreased frequency of NK cells with a reduction of function can be observed in the liver of both murine cirrhotic models ( 22 ) and cirrhotic patients ( 4 , 23 , 24 ). In this study, the proportion of the NK cluster cells decreased significantly in the cirrhotic group, which was consistent with previous findings.…”

Targeting glutamine metabolism in hepatic stellate cells alleviates liver fibrosis

“…The important role played by glutamate in HSCs in various liver diseases has been recently reported. Choi WM et al [27] . found that the uptake of glutamate was increased in activated HSCs and that mGluR5 activation enhanced the cytotoxicity of NK cells.…”

Targeting SYK of monocyte-derived macrophages regulates liver fibrosis via crosstalking with Erk/Hif1α and remodeling liver inflammatory environment

“…Different cell-targeted Erk pathways may play a heterogeneous role in the progression of fibrosis. In NK cells, mGluR5 regulates the expression of IFN-γ through Mek/Erk, thereby activating the cytotoxicity of NK cells to HSC and driving the resolution of liver fibrosis [ 42 ]. ALOX-5 relies on the Erk signal axis to promote the secretion of LTB 4 and LTC 4 to induce HSC activation.…”