Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 11, Pages 4346-4360Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI87545
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Funding
- DFG [SFB796, SPP1656, SFB1181-A08, BE3686/2, KR4391/1-1, KFO257]
- Interdisciplinary Center for Clinical Research of the University Erlangen-Nuremberg
- National Health and Medical Research Council of Australia [1057905, 1105754, 9000220]
- Victorian Government Operational Infrastructure Support Scheme
- Dr. Werner Jackstadt-Stiftung
- Fresenius Medical Care Germany
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Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor interacting protein (RIP) lcinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-gamma in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases.
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