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Updated: Jul 5, 2025
3D Imaging of the Liver Extracellular Matrix in a Mouse Model of Non-Alcoholic Steatohepatitis
Published on: February 25, 2022
Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of HSC
Yujia Xia1,2, Yu Wang2,3, Qi Xiong3
1Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Background And Aims:
Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a reversible stage of liver disease accompanied by inflammatory cell infiltration. Neutrophils extrude a meshwork of chromatin fibers to establish neutrophil extracellular traps (NETs), which play important roles in inflammatory response regulation. Our previous work demonstrated that NETs promote HCC in MASH. However, it is still unknown if NETs play a role in the molecular mechanisms of liver fibrosis.
Approach And Results:
Following 12 weeks of Western diet/carbon tetrachloride, MASH fibrosis was identified in C57BL/6 mice with increased NET formation. However, NET depletion using DNase I treatment or mice knocked out for peptidyl arginine deaminase type IV significantly attenuated the development of MASH fibrosis. NETs were demonstrated to induce HSCs activation, proliferation, and migration through augmented mitochondrial and aerobic glycolysis to provide additional bioenergetic and biosynthetic supplies. Metabolomic analysis revealed markedly an altered metabolic profile upon NET stimulation of HSCs that were dependent on arachidonic acid metabolism. Mechanistically, NET stimulation of toll-like receptor 3 induced cyclooxygenase-2 activation and prostaglandin E2 production with subsequent HSC activation and liver fibrosis. Inhibiting cyclooxygenase-2 with celecoxib reduced fibrosis in our MASH model.
Conclusions:
Our findings implicate NETs playing a critical role in the development of MASH hepatic fibrosis by inducing metabolic reprogramming of HSCs through the toll-like receptor 3/cyclooxygenase-2/cyclooxygenase-2 pathway. Therefore, NET inhibition may represent an attractive treatment target for MASH liver fibrosis.
Insights
Neutrophil extracellular traps (NETs) drive metabolic dysfunction-associated steatohepatitis (MASH) fibrosis by reprogramming liver cells. Inhibiting NETs may offer a novel therapeutic strategy for MASH liver fibrosis.
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis involves inflammation and is potentially reversible.
- Neutrophil extracellular traps (NETs) are implicated in inflammatory processes and hepatocellular carcinoma (HCC) in MASH.
- The role of NETs in the molecular mechanisms of MASH liver fibrosis remains unclear.
Purpose of the Study:
- To investigate the role of NETs in the development of MASH-associated liver fibrosis.
- To elucidate the molecular mechanisms by which NETs contribute to liver fibrosis.
- To explore potential therapeutic targets for MASH fibrosis.
Main Methods:
- Induction of MASH fibrosis in C57BL/6 mice using a Western diet/carbon tetrachloride model.
- NET depletion via DNase I treatment or using peptidyl arginine deaminase type IV knockout mice.
- Assessment of hepatic stellate cell (HSC) activation, proliferation, and migration.
- Metabolomic analysis of NET-stimulated HSCs.
- Investigation of the Toll-like receptor 3 (TLR3)/cyclooxygenase-2 (COX2) pathway.
- Inhibition of COX2 using celecoxib.
Main Results:
- MASH fibrosis and increased NET formation were observed in mice after 12 weeks.
- NET depletion significantly attenuated MASH fibrosis development.
- NETs induced HSC activation, proliferation, and migration via enhanced mitochondrial and aerobic glycolysis.
- NET stimulation altered HSC metabolism, dependent on arachidonic acid metabolism.
- NETs activated TLR3, leading to COX2 and prostaglandin E2 production, promoting HSC activation and fibrosis.
- Celecoxib treatment reduced fibrosis in the MASH model.
Conclusions:
- NETs play a critical role in MASH hepatic fibrosis development.
- NETs induce HSC metabolic reprogramming through the TLR3/COX2 pathway.
- NET inhibition presents a potential therapeutic strategy for MASH liver fibrosis.
