RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis

James A Rickard; Joanne A O'Donnell; Joseph M Evans; Najoua Lalaoui; Ashleigh R Poh; TeWhiti Rogers; James E Vince; Kate E Lawlor; Robert L Ninnis; Holly Anderton; Cathrine Hall; Sukhdeep K Spall; Toby J Phesse; Helen E Abud; Louise H Cengia; Jason Corbin; Sandra Mifsud; Ladina Di Rago; Donald Metcalf; Matthias Ernst; Grant Dewson; Andrew W Roberts; Warren S Alexander; James M Murphy; Paul G Ekert; Seth L Masters; David L Vaux; Ben A Croker; Motti Gerlic; John Silke

doi:10.1016/j.cell.2014.04.019

RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis

Cell. 2014 May 22;157(5):1175-88. doi: 10.1016/j.cell.2014.04.019. Epub 2014 May 8.

Authors

James A Rickard¹, Joanne A O'Donnell¹, Joseph M Evans², Najoua Lalaoui¹, Ashleigh R Poh¹, TeWhiti Rogers³, James E Vince¹, Kate E Lawlor¹, Robert L Ninnis¹, Holly Anderton¹, Cathrine Hall¹, Sukhdeep K Spall¹, Toby J Phesse¹, Helen E Abud⁴, Louise H Cengia¹, Jason Corbin¹, Sandra Mifsud¹, Ladina Di Rago¹, Donald Metcalf¹, Matthias Ernst¹, Grant Dewson¹, Andrew W Roberts⁵, Warren S Alexander¹, James M Murphy¹, Paul G Ekert¹, Seth L Masters¹, David L Vaux¹, Ben A Croker⁶, Motti Gerlic⁷, John Silke⁸

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
² The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Biochemistry, La Trobe University, Bundoora, VIC 3086, Australia.
³ Department of Pathology, University of Melbourne, Parkville, VIC 3050, Australia.
⁴ Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC 3800, Australia.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.

PMID: 24813849
DOI: 10.1016/j.cell.2014.04.019

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Caspase 8 / metabolism
Cell Death
Genes, Lethal*
Hematopoiesis*
Inflammation / metabolism*
Liver / metabolism
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Myeloid Differentiation Factor 88 / genetics
Myeloid Differentiation Factor 88 / metabolism
Protein Kinases / genetics
Protein Kinases / metabolism
Receptor-Interacting Protein Serine-Threonine Kinases / genetics
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
Receptors, Tumor Necrosis Factor, Type I / metabolism
Tumor Necrosis Factors / metabolism

Substances

Myd88 protein, mouse
Myeloid Differentiation Factor 88
Receptors, Tumor Necrosis Factor, Type I
Tnfrsf1a protein, mouse
Tumor Necrosis Factors
MLKL protein, mouse
Protein Kinases
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk1 protein, mouse
Ripk3 protein, mouse
Casp8 protein, mouse
Caspase 8