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

Feixue Wang; Xiang Zhang; Weixin Liu; Yunfei Zhou; Wenchao Wei; Dabin Liu; Chi Chun Wong; Joseph J Y Sung; Jun Yu

doi:10.1016/j.jcmgh.2021.08.019

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

Cell Mol Gastroenterol Hepatol. 2022;13(1):257-274. doi: 10.1016/j.jcmgh.2021.08.019. Epub 2021 Sep 20.

Authors

Feixue Wang¹, Xiang Zhang¹, Weixin Liu¹, Yunfei Zhou¹, Wenchao Wei¹, Dabin Liu¹, Chi Chun Wong¹, Joseph J Y Sung², Jun Yu³

Affiliations

¹ Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China.
² Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China; Lee Kong Chian School of Medicine, Nanyang Technology University, Singapore.
³ Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: junyu@cuhk.edu.hk.

Abstract

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.

Keywords: Cytokine; JAK/STAT; Natural Killer Cell; Nonalcoholic Steatohepatitis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diet, High-Fat
Janus Kinases / metabolism
Killer Cells, Natural
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / metabolism
STAT Transcription Factors / metabolism
Signal Transduction

Substances

STAT Transcription Factors
Janus Kinases