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

Autor: Wenchao Wei, Chi Chun Wong, Xiang Zhang, Jun Yu, Weixin Liu, Feixue Wang, Yunfei Zhou, Dabin Liu, Joseph J.Y. Sung
Jazyk: angličtina
Rok vydání: 2022
Předmět:
medicine.medical_treatment
Nonalcoholic Steatohepatitis
AST
aspartate aminotransferase
RC799-869
IL12
interleukin 12
Non-alcoholic Fatty Liver Disease
TBARS
thiobarbituric acid reactive substances
NK cell
natural killer cell
NF-κB
nuclear factor kappa B
Original Research
Activated Natural Killer Cell
JAK-STAT
Janus kinase-signal transducer and activator of transcription
Chemistry
Gastroenterology
JAK-STAT signaling pathway
ELISA
enzyme-linked immunosorbent assay
TG
triglycerides
Diseases of the digestive system. Gastroenterology
Killer Cells
Natural
medicine.anatomical_structure
Cytokine
Interleukin 12
LPS
lipopolysaccharide
FITC
fluorescein isothiocyanate
GM-CSF
granulocyte-macrophage colony-stimulating factor
NASH
nonalcoholic steatohepatitis
CDHF
choline-deficient high-fat diet
MFI
mean fluorescent intensity
CCL5
Natural killer cell
ROS
reactive oxygen species
ALT
alanine aminotransferase
medicine
KEGG
Kyoto encyclopedia of genes and genomes
Humans
MoMF
monocyte derived macrophage
MCD
methionine- and choline-deficient
IFN-γ
interferon gamma
Hepatology
nutritional and metabolic diseases
NADPH
nicotinamide adenine dinucleotide phosphate
medicine.disease
NKG2D
Ig
immunoglobulin
JAK/STAT
Cancer research
NAFLD
nonalcoholic fatty liver disease
Steatohepatitis
HCC
hepatocellular carcinoma
NKT cell
natural killer T cell
Natural Killer Cell
Zdroj: Cellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 257-274 (2022)
Cellular and Molecular Gastroenterology and Hepatology
Popis: 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.
Graphical abstract
Databáze: OpenAIRE
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