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 ErnstGrant 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1175-1188
Number of pages14
Issue number5
StatePublished - 22 May 2014


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