Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary

Background & Aims: Hepatic immune microenvironment plays a pivotal role in the development of nonalcoholic steatohepatitis (NASH). However, the role of natural killer (NK) cells, accounting for 10%–20% of liver lymphocytes, in NASH is still unclear. In this study, we aim to investigate the f...

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Autores principales:	Feixue Wang, Xiang Zhang, Weixin Liu, Yunfei Zhou, Wenchao Wei, Dabin Liu, Chi Chun Wong, Joseph J.Y. Sung, Jun Yu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Nonalcoholic Steatohepatitis Natural Killer Cell Cytokine JAK/STAT Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/a8d5c23488ee40f7bb04e548f08f5f43
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spelling	oai:doaj.org-article:a8d5c23488ee40f7bb04e548f08f5f432021-11-14T04:34:17ZActivated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary2352-345X10.1016/j.jcmgh.2021.08.019https://doaj.org/article/a8d5c23488ee40f7bb04e548f08f5f432022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001867https://doaj.org/toc/2352-345XBackground & Aims: Hepatic immune microenvironment plays a pivotal role in the development of nonalcoholic steatohepatitis (NASH). However, the role of natural killer (NK) cells, accounting for 10%–20% of liver lymphocytes, in NASH is still unclear. In this study, we aim to investigate the functional significance of NK cells in NASH evolution. Methods: NASH was induced in mice fed methionine- and choline-deficient diet (MCD), choline-deficient high-fat diet (CD-HFD), or high-fat diet with streptozotocin injection (STAM model). NK cell deficient mice (Nfil3-/-) and neutralization antibody (PK136) were used in this study. Results: Activated liver NK cells were identified with increased expression of NKG2D, CD107a, and interferon-γ but decreased inhibitory NKG2A. With NK cell deficiency Nfil3-/- mice, the absence of NK cells ameliorated both MCD- and CDHF- induced NASH development with significantly decreased hepatic triglycerides, peroxides, alanine aminotransferase, and aspartate aminotransferase compared with Nfil3+/+ mice. Further molecular analysis unveiled suppressed pro-inflammatory cytokines and associated signaling. Mechanistically, NK cells isolated from NASH liver secreted higher levels of pro-inflammatory cytokines (interferon-γ, interleukin 1β, interleukin 12, CCL4, CCL5, and granulocyte-macrophage colony-stimulating factor), which could activate hepatic JAK-STAT1/3 and nuclear factor kappa B signaling and induce hepatocyte damage evidenced by elevated reactive oxygen species and apoptosis rate. Moreover, neutralization antibody PK136-dependent NK cell depletion can significantly alleviate MCD-induced steatohepatitis with suppressed cytokine levels and JAK-STAT1/3 activity. Conclusions: NK cells in NASH liver are activated with a more pro-inflammatory cytokine milieu and promote NASH development via cytokine-JAK-STAT1/3 axis. Modulation of NK cells provides a potential therapeutic strategy for NASH.Feixue WangXiang ZhangWeixin LiuYunfei ZhouWenchao WeiDabin LiuChi Chun WongJoseph J.Y. SungJun YuElsevierarticleNonalcoholic SteatohepatitisNatural Killer CellCytokineJAK/STATDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 257-274 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Nonalcoholic Steatohepatitis Natural Killer Cell Cytokine JAK/STAT Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Nonalcoholic Steatohepatitis Natural Killer Cell Cytokine JAK/STAT Diseases of the digestive system. Gastroenterology RC799-869 Feixue Wang Xiang Zhang Weixin Liu Yunfei Zhou Wenchao Wei Dabin Liu Chi Chun Wong Joseph J.Y. Sung Jun Yu Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary
description	Background & Aims: Hepatic immune microenvironment plays a pivotal role in the development of nonalcoholic steatohepatitis (NASH). However, the role of natural killer (NK) cells, accounting for 10%–20% of liver lymphocytes, in NASH is still unclear. In this study, we aim to investigate the functional significance of NK cells in NASH evolution. Methods: NASH was induced in mice fed methionine- and choline-deficient diet (MCD), choline-deficient high-fat diet (CD-HFD), or high-fat diet with streptozotocin injection (STAM model). NK cell deficient mice (Nfil3-/-) and neutralization antibody (PK136) were used in this study. Results: Activated liver NK cells were identified with increased expression of NKG2D, CD107a, and interferon-γ but decreased inhibitory NKG2A. With NK cell deficiency Nfil3-/- mice, the absence of NK cells ameliorated both MCD- and CDHF- induced NASH development with significantly decreased hepatic triglycerides, peroxides, alanine aminotransferase, and aspartate aminotransferase compared with Nfil3+/+ mice. Further molecular analysis unveiled suppressed pro-inflammatory cytokines and associated signaling. Mechanistically, NK cells isolated from NASH liver secreted higher levels of pro-inflammatory cytokines (interferon-γ, interleukin 1β, interleukin 12, CCL4, CCL5, and granulocyte-macrophage colony-stimulating factor), which could activate hepatic JAK-STAT1/3 and nuclear factor kappa B signaling and induce hepatocyte damage evidenced by elevated reactive oxygen species and apoptosis rate. Moreover, neutralization antibody PK136-dependent NK cell depletion can significantly alleviate MCD-induced steatohepatitis with suppressed cytokine levels and JAK-STAT1/3 activity. Conclusions: NK cells in NASH liver are activated with a more pro-inflammatory cytokine milieu and promote NASH development via cytokine-JAK-STAT1/3 axis. Modulation of NK cells provides a potential therapeutic strategy for NASH.
format	article
author	Feixue Wang Xiang Zhang Weixin Liu Yunfei Zhou Wenchao Wei Dabin Liu Chi Chun Wong Joseph J.Y. Sung Jun Yu
author_facet	Feixue Wang Xiang Zhang Weixin Liu Yunfei Zhou Wenchao Wei Dabin Liu Chi Chun Wong Joseph J.Y. Sung Jun Yu
author_sort	Feixue Wang
title	Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary
title_short	Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary
title_full	Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary
title_fullStr	Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary
title_full_unstemmed	Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary
title_sort	activated natural killer cell promotes nonalcoholic steatohepatitis through mediating jak/stat pathwaysummary
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/a8d5c23488ee40f7bb04e548f08f5f43
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Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT PathwaySummary

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