4.7 Article

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

Journal

Publisher

ELSEVIER INC
DOI: 10.1016/j.jcmgh.2021.08.019

Keywords

Nonalcoholic Steatohepatitis; Natural Killer Cell; Cytokine; JAK/STAT

Funding

  1. RGC Theme-based Research Scheme Hong Kong [T12-703/19-R]
  2. RGC Collaborative Research Fund [C4041-17GF, C7026-18GF]
  3. HMRF Hong Kong [07181256]
  4. Vice-Chancellor's Discretionary Fund CUHK

Ask authors/readers for more resources

Activated NK cells in the liver promote NASH development by releasing pro-inflammatory cytokines and enhancing NASH progression through the cytokine-JAK-STAT1/3 axis. Modulation of NK cells may serve as a potential therapeutic strategy for NASH.
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 (CDHFD), 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- gamma 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 proinflammatory cytokines and associated signaling. Mechanistically, NK cells isolated from NASH liver secreted higher levels of pro-inflammatory cytokines (interferon-gamma, interleukin 1 beta, 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available