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Activated Natural Killer Cell Promotes Nonalcoholic Steatohepatitis Through Mediating JAK/STAT Pathway
Feixue Wang1, Xiang Zhang1, Weixin Liu1
1Institute 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.
Cellular and Molecular Gastroenterology and Hepatology
|September 10, 2021
Summary
Natural killer (NK) cells promote nonalcoholic steatohepatitis (NASH) development by secreting pro-inflammatory cytokines that activate hepatic signaling pathways. Depleting NK cells alleviates NASH, suggesting they are a potential therapeutic target.
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Nonalcoholic steatohepatitis (NASH) pathogenesis involves the hepatic immune microenvironment.
- The specific role of natural killer (NK) cells in NASH progression remains unclear.
Purpose of the Study:
- To investigate the functional significance of NK cells in the evolution of NASH.
- To elucidate the mechanisms by which NK cells contribute to NASH development.
Main Methods:
- NASH was induced in mice using methionine- and choline-deficient (MCD) or choline-deficient high-fat (CD-HFD) diets, and high-fat diet with streptozotocin (STAM model).
- NK cell deficiency was achieved using Nfil3-/- mice, and NK cells were depleted using the PK136 neutralization antibody.
Main Results:
- Activated liver NK cells exhibited increased NKG2D, CD107a, and interferon-γ expression.
- NK cell deficiency ameliorated NASH development, reducing hepatic triglycerides, peroxides, and liver enzymes.
- NASH-associated NK cells secreted pro-inflammatory cytokines, activating hepatic JAK-STAT1/3 and NF-κB signaling, leading to hepatocyte damage.
Conclusions:
- Activated NK cells in the NASH liver promote disease progression through a pro-inflammatory cytokine-JAK-STAT1/3 axis.
- Modulating NK cell activity presents a potential therapeutic strategy for NASH.
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