Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells
Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells
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DOI：
10.1002/hep.31875
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发表时间：
2021-07-29
期刊：
影响因子：
13.5
通讯作者：
Jeong, Won-Il
中科院分区：
文献类型：
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作者：
Choi, Won-Mook;Ryu, Tom;Jeong, Won-Il
背景与目的近年来，肝星状细胞中谷氨酸和代谢型谷氨酸受体5（metabotropic glutamate receptor 5，mGluR 5）在多种肝脏疾病中的重要作用已被报道，但其在肝纤维化中的作用机制尚不清楚。在这里，我们报告说，mGluR 5在自然杀伤（NK）细胞的激活，通过增加细胞毒性和干扰素-γ（IFN-γ）的生产在小鼠和人类减弱肝纤维化。方法和结果注射四氯化碳（CCl 4）2周或5周蛋氨酸缺乏和胆碱缺乏饮食后，mGluR 5基因敲除小鼠的肝纤维化加重，与野生型小鼠相比，NK细胞的频率显著降低。一致地，NK细胞特异性mGluR 5敲除小鼠加重了CCl 4诱导的肝纤维化，IFN-γ的产生减少。相反，NK细胞中mGluR 5的体外激活显著增加了抗纤维化相关基因的表达，包括Ifng、Prf 1（穿孔素）和Klrk 1（杀伤细胞凝集素样受体K1），并通过丝裂原激活的细胞外信号调节激酶/细胞外信号相关激酶途径产生IFN-γ，从而增加了对活化HSC的细胞毒性。然而，我们发现活化的HSC中谷氨酸的摄取增加，导致细胞外谷氨酸的短缺和NK细胞中mGluR 5的刺激减少。因此，这可以使HSC在晚期肝纤维化中逃避NK细胞的细胞毒性。在体内，mGluR 5的药理学激活通过恢复NK细胞的细胞毒性加速CCl 4诱导的肝纤维化消退。在人类中，mGluR 5激活增强了从健康供体分离的NK细胞的细胞毒性，但没有从NK细胞中mGluR 5表达显著降低的肝硬化患者分离的NK细胞的细胞毒性。结论mGluR 5通过增强NK细胞的杀伤活性在抗肝纤维化中发挥重要作用，可作为抗肝纤维化的潜在治疗靶点。
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-gamma (IFN-gamma) 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-gamma. 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-gamma 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.