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 E Corbin, Sandra Mifsud, Ladina Di Rago, Donald Metcalf, Matthias R 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

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339 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1175 - 1188
Number of pages14
JournalCell
Volume157
Issue number5
DOIs
Publication statusPublished - 2014

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