Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress
| Autor: | Michael Kinter, Gordon H. Royce, Sabira Mohammed, Nidheesh Thadathil, Ramasamy Selvarani, Evan H Nicklas, Sathyaseelan S. Deepa, Arlan Richardson |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Carcinoma Hepatocellular Necroptosis Inflammation medicine.disease_cause Biochemistry Article 03 medical and health sciences Mice 0302 clinical medicine Fibrosis Non-alcoholic Fatty Liver Disease Physiology (medical) medicine Animals STAT3 biology business.industry Fatty liver Liver Neoplasms medicine.disease digestive system diseases Mice Inbred C57BL Disease Models Animal Oxidative Stress 030104 developmental biology Liver biology.protein Cancer research Tumor necrosis factor alpha Steatohepatitis medicine.symptom business 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Free Radic Biol Med |
| ISSN: | 1873-4596 |
| Popis: | Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1(−/−) or Sod1KO mice) have increased oxidative stress, show accelerated aging and develop spontaneous hepatocellular carcinoma with age (HCC). Similar to humans, HCC development in Sod1KO mice progresses from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) with fibrosis, which eventually progresses to HCC. Oxidative stress plays a role in NAFLD to NASH progression, and liver inflammation is the main mechanism that drives the disease progression from NASH to fibrosis. Because necroptosis is a major source of inflammation, we tested the hypothesis that increased necroptosis in the liver plays a role in increased inflammation and fibrosis in Sod1KO mice. Phosphorylation of MLKL (P- MLKL), a well-accepted marker of necroptosis, and expression of MLKL protein were significantly increased in the livers of Sod1KO mice compared to wild type (WT) mice indicating increased necroptosis. Similarly, phosphorylation of RIPK3 and RIPK3 protein levels were also significantly increased. Markers of pro-inflammatory M1 macrophages, NLRP3 inflammasome, and transcript levels of pro-inflammatory cytokines and chemokines, e.g., TNFα, IL-6, IL-1β, and Ccl2 that are associated with human NASH, were significantly increased. Expression of antioxidant enzymes and heat shock proteins, and markers of fibrosis and oncogenic transcription factor STAT3 were also upregulated and autophagy was downregulated in the livers of Sod1KO mice. Short term treatment of Sod1KO mice with necrostatin-1s (Nec-1s), a necroptosis inhibitor, reversed these conditions. Our data show for the first time that necroptosis-mediated inflammation contributes to fibrosis in a mouse model of increased oxidative stress and accelerated aging, that also exhibits progressive HCC development. |
| Databáze: | OpenAIRE |
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