Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, Republic of Korea.
Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Hepatology. 2021 Oct;74(4):2170-2185. doi: 10.1002/hep.31875. Epub 2021 Jul 29.
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.
Following 2-week injection of carbon tetrachloride (CCl ) 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 CCl -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 CCl -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.
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.
谷氨酸和代谢型谷氨酸受体 5（mGluR5）在肝星状细胞（HSCs）中的重要作用已在各种肝脏疾病中得到报道；然而，谷氨酰胺/谷氨酸代谢与肝纤维化中 mGluR5 之间的联系机制尚不清楚。在这里，我们报告称，自然杀伤（NK）细胞中 mGluR5 的激活通过增加细胞毒性和干扰素-γ（IFN-γ）的产生，在小鼠和人类中均可减轻肝纤维化。
在连续 2 周注射四氯化碳（CCl ）或 5 周蛋氨酸缺乏和胆碱缺乏饮食后，与野生型小鼠相比，mGluR5 敲除小鼠的 NK 细胞频率显著降低，其肝纤维化程度更为严重。同样，NK 细胞特异性 mGluR5 敲除小鼠的 CCl 诱导的肝纤维化加重，IFN-γ产生减少。相反，体外激活 NK 细胞中的 mGluR5 通过丝裂原活化的细胞外信号调节激酶/细胞外信号相关激酶途径显著增加包括 Ifng、Prf1（穿孔素）和 Klrk1（杀伤细胞凝集素样受体 K1）在内的抗纤维化相关基因的表达和 IFN-γ的产生，从而增加对活化的 HSCs 的细胞毒性。然而，我们发现活化的 HSCs 中谷氨酸的摄取增加，导致细胞外谷氨酸短缺，从而减少 NK 细胞中 mGluR5 的刺激。因此，这可以使 HSCs 在晚期肝纤维化中逃避 NK 细胞的细胞毒性。在体内，通过恢复 NK 细胞的细胞毒性，mGluR5 的药理学激活加速了 CCl 诱导的肝纤维化消退。在人类中，mGluR5 的激活增强了来自健康供体的 NK 细胞的细胞毒性，但对 NK 细胞中 mGluR5 表达显著降低的肝硬化患者的 NK 细胞没有作用。
mGluR5 通过增强 NK 细胞的细胞毒性在减轻肝纤维化方面发挥重要作用，这可作为肝纤维化的潜在治疗靶点。
