RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis Academic Article uri icon

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

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

publication date

  • May 2014

published in