한빛사논문
- 조회688
Won-Mook Choi,1,2* Tom Ryu,1* Jun-Hee Lee,1 Young-Ri Shim,1 Myung-Ho Kim,1 Hee-Hoon Kim,1 Ye-Eun Kim,1 Keungmo Yang,1 Kyurae Kim,1 Sung Eun Choi,1 Won Kim,3 Seok-Hwan Kim,4 Hyuk Soo Eun,5 and Won-Il Jeong1,6
1Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 34141, Republic of Korea
2Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
3Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae
Medical Center, Seoul 07061, Republic of Korea
4Department of Surgery, Chungnam National University, College of Medicine, Daejeon 35015, Republic of Korea.
5Department of Internal Medicine, Chungnam National University, School of Medicine, Daejeon 35015,
Republic of Korea.
6Biomedical Research Center, KAIST, Daejeon 34141, Republic of Korea.
*Authors equally contributed to this study
Correspondence: Prof. Won‐Il Jeong, D.V.M., Ph.D., Prof. Hyuk Soo Eun, M.D., Ph.D., Prof. Seok‐Hwan Kim, M.D., Ph.D.
Abstract
Background & Aims
The important roles of glutamate and metabotropic glutamate receptor 5 (mGluR5) in hepatic stellate cells (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 & Results
Following 2‐week injection of carbon tetrachloride (CCl4) or 5‐week methionine‐ and choline‐deficient diet, liver fibrosis was more aggravated in mGluR5 knockout (KO) mice with significantly decreased frequency of NK cells compared with wild type mice. Consistently, NK cell‐specific mGluR5 KO 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, and Klrk1 and the production of IFN‐γ via the MEK/ERK 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 cirrhotic patients 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.
논문정보
- Research article
- 2021년 05월 (BRIC 등록일 2021-05-10)
- 국내 연구진
- 의약학 > 응용의학
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