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.
James A Rickard  1 ,  Joanne A O'Donnell  1 ,  Joseph M Evans  2 ,  Najoua Lalaoui  1 ,  Ashleigh R Poh  1 ,  TeWhiti Rogers  3 ,  James E Vince  1 ,  Kate E Lawlor  1 ,  Robert L Ninnis  1 ,  Holly Anderton  1 ,  Cathrine Hall  1 ,  Sukhdeep K Spall  1 ,  Toby J Phesse  1 ,  Helen E Abud  4 ,  Louise H Cengia  1 ,  Jason Corbin  1 ,  Sandra Mifsud  1 ,  Ladina Di Rago  1 ,  Donald Metcalf  1 ,  Matthias Ernst  1 ,  Grant Dewson  1 ,  Andrew W Roberts  5 ,  Warren S Alexander  1 ,  James M Murphy  1 ,  Paul G Ekert  1 ,  Seth L Masters  1 ,  David L Vaux  1 ,  Ben A Croker  6 ,  Motti Gerlic  7 ,  John Silke  8
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: [email protected].
  • 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: [email protected].
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.