title: RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis.
abstract: Upon ligand binding, RIPK1 is recruited to tumor necrosis factor receptor superfamily (TNFRSF) and Toll-like receptor (TLR) complexes promoting prosurvival and inflammatory signaling. RIPK1 also directly regulates caspase-8-mediated apoptosis or, if caspase-8 activity is blocked, RIPK3-MLKL-dependent necroptosis. We show that C57BL/6 Ripk1(-/-) mice die at birth of systemic inflammation that was not transferable by the hematopoietic compartment. However, Ripk1(-/-) progenitors failed to engraft lethally irradiated hosts properly. Blocking TNF reversed this defect in emergency hematopoiesis but, surprisingly, Tnfr1 deficiency did not prevent inflammation in Ripk1(-/-) neonates. Deletion of Ripk3 or Mlkl, but not Casp8, prevented extracellular release of the necroptotic DAMP, IL-33, and reduced Myd88-dependent inflammation. Reduced inflammation in the Ripk1(-/-)Ripk3(-/-), Ripk1(-/-)Mlkl(-/-), and Ripk1(-/-)Myd88(-/-) mice prevented neonatal lethality, but only Ripk1(-/-)Ripk3(-/-)Casp8(-/-) mice survived past weaning. These results reveal a key function for RIPK1 in inhibiting necroptosis and, thereby, a role in limiting, not only promoting, inflammation.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: James A
authors.initials: JA
authors.lastname: Rickard
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Joanne A
authors.initials: JA
authors.lastname: O'Donnell
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Biochemistry, La Trobe University, Bundoora, VIC 3086, Australia.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Evans
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Najoua
authors.initials: N
authors.lastname: Lalaoui
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Ashleigh R
authors.initials: AR
authors.lastname: Poh
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: TeWhiti
authors.initials: T
authors.lastname: Rogers
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lawlor
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ninnis
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Holly
authors.initials: H
authors.lastname: Anderton
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Hall
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Sukhdeep K
authors.initials: SK
authors.lastname: Spall
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Toby J
authors.initials: TJ
authors.lastname: Phesse
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Abud
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Louise H
authors.initials: LH
authors.lastname: Cengia
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Corbin
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mifsud
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Ladina
authors.initials: L
authors.lastname: Di Rago
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Dewson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia; Faculty of Medicine, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: James M
authors.initials: JM
authors.lastname: Murphy
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ekert
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors.forename: David L
authors.initials: DL
authors.lastname: Vaux
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia; Division of Hematology and Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Croker
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia; Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. Electronic address: mgerlic@post.tau.ac.il.
authors.forename: Motti
authors.initials: M
authors.lastname: Gerlic
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia. Electronic address: j.silke@latrobe.edu.au.
authors.forename: John
authors.initials: J
authors.lastname: Silke
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death; D005804:Genes, Lethal; D006410:Hematopoiesis; D007249:Inflammation / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D048069:Tumor Necrosis Factors; C570694:MLKL protein, mouse; D011494:Protein Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; C485615:Ripk3 protein, mouse; C505526:Casp8 protein, mouse; D053181:Caspase 8