title: The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis.
abstract: 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) kinase-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-γ 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.
authors.forename: Claudia
authors.initials: C
authors.lastname: Günther
authors.forename: Gui-Wei
authors.initials: GW
authors.lastname: He
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Kremer
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Petrie
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenabeele
authors.forename: Andreas
authors.initials: A
authors.lastname: Linkermann
authors.forename: Christopher
authors.initials: C
authors.lastname: Poremba
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schleicher
authors.forename: Christin
authors.initials: C
authors.lastname: Dewitz
authors.forename: Stefan
authors.initials: S
authors.lastname: Krautwald
authors.forename: Markus F
authors.initials: MF
authors.lastname: Neurath
authors.forename: Christoph
authors.initials: C
authors.lastname: Becker
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirtz
mesh_terms: D000818:Animals; D019693:Hepatitis, Autoimmune / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D022781:Hepatocytes / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism
chemical_list: C573415:IFNG protein, human; C000611649:IFNG protein, mouse; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; C570693:MLKL protein, human; C570694:MLKL protein, mouse; D011494:Protein Kinases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse