{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:46:44Z","timestamp":1792788404620,"version":"4.5.0"},"reference-count":40,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T00:00:00Z","timestamp":1627516800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>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\u2010\u03b3 (IFN\u2010\u03b3) production in both mice and humans.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Following 2\u2010week injection of carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>) or 5\u2010week methionine\u2010deficient and choline\u2010deficient diet, liver fibrosis was more aggravated in mGluR5 knockout mice with significantly decreased frequency of NK cells compared with wild\u2010type mice. Consistently, NK cell\u2013specific mGluR5 knockout mice had aggravated CCl<jats:sub>4<\/jats:sub>\u2010induced liver fibrosis with decreased production of IFN\u2010\u03b3. Conversely, <jats:italic toggle=\"yes\">in vitro<\/jats:italic> activation of mGluR5 in NK cells significantly increased the expression of anti\u2010fibrosis\u2010related genes including <jats:italic toggle=\"yes\">Ifng<\/jats:italic>, <jats:italic toggle=\"yes\">Prf1<\/jats:italic> (perforin), and <jats:italic toggle=\"yes\">Klrk1<\/jats:italic> (killer cell lectin like receptor K1) and the production of IFN\u2010\u03b3 through the mitogen\u2010activated extracellular signal\u2010regulated kinase\/extracellular signal\u2010related 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. <jats:italic toggle=\"yes\">In vivo<\/jats:italic>, pharmacologic activation of mGluR5 accelerated CCl<jats:sub>4<\/jats:sub>\u2010induced 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31875","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T13:06:46Z","timestamp":1619874406000},"page":"2170-2185","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":61,"title":["Metabotropic Glutamate Receptor 5 in Natural Killer Cells Attenuates Liver Fibrosis by Exerting Cytotoxicity to Activated Stellate Cells"],"prefix":"10.1097","volume":"74","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9158-1765","authenticated-orcid":false,"given":"Won\u2010Mook","family":"Choi","sequence":"first","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"},{"name":"Department of Gastroenterology,Liver Center,Asan Medical Center,University of Ulsan College of Medicine,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Ryu","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3080-4240","authenticated-orcid":false,"given":"Jun\u2010Hee","family":"Lee","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young\u2010Ri","family":"Shim","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myung\u2010Ho","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hee\u2010Hoon","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye Eun","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keungmo","family":"Yang","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyurae","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung Eun","family":"Choi","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Research,Graduate School of Medical Science and Engineering,KAIST,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2926-1007","authenticated-orcid":false,"given":"Won","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,Seoul Metropolitan Government Seoul National University Boramae Medical Center,Seoul,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seok\u2010Hwan","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Surgery,College of Medicine,Chungnam National University,Daejeon,Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyuk Soo","family":"Eun","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine,School of Medicine,Chungnam National University,Daejeon,Republic of 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