title: Divergent effects of RIP1 or RIP3 blockade in murine models of acute liver injury.
abstract: Necroptosis is a recently described Caspase 8-independent method of cell death that denotes organized cellular necrosis. The roles of RIP1 and RIP3 in mediating hepatocyte death from acute liver injury are incompletely defined. Effects of necroptosis blockade were studied by separately targeting RIP1 and RIP3 in diverse murine models of acute liver injury. Blockade of necroptosis had disparate effects on disease outcome depending on the precise etiology of liver injury and component of the necrosome targeted. In ConA-induced autoimmune hepatitis, RIP3 deletion was protective, whereas RIP1 inhibition exacerbated disease, accelerated animal death, and was associated with increased hepatocyte apoptosis. Conversely, in acetaminophen-mediated liver injury, blockade of either RIP1 or RIP3 was protective and was associated with lower NLRP3 inflammasome activation. Our work highlights the fact that diverse modes of acute liver injury have differing requirements for RIP1 and RIP3; moreover, within a single injury model, RIP1 and RIP3 blockade can have diametrically opposite effects on tissue damage, suggesting that interference with distinct components of the necrosome must be considered separately.
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Deutsch
authors.affiliation: Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Graffeo
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Rokosh
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pansari
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ochi
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Levie
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: E
authors.initials: E
authors.lastname: Van Heerden
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Tippens
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Greco
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Barilla
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Tomkötter
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Zambirinis
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Avanzi
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Gulati
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Pachter
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Torres-Hernandez
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Eisenthal
authors.affiliation: S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Daley
authors.affiliation: 1] S Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, NY, USA [2] Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Miller
mesh_terms: D000082:Acetaminophen; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D018932:Chemokine CCL2 / Q000097:blood; D003208:Concanavalin A; D004195:Disease Models, Animal; D020690:GTPase-Activating Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000235:genetics*; D022781:Hepatocytes / Q000473:pathology; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000293:injuries* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009336:Necrosis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D002352:Carrier Proteins; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D020690:GTPase-Activating Proteins; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C490620:Ralbp1 protein, mouse; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D003208:Concanavalin A; D000082:Acetaminophen; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D053181:Caspase 8