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

Rickard, JA; O&#39;Donnell, JA; Evans, JM; Lalaoui, N; Poh, AR; Rogers, T; Vince, JE; Lawlor, KE; Ninnis, RL; Anderton, H; Hall, CJ; Spall, SK; Phesse, TJ; Abud, HE; Cengia, LH; Corbin, J; Mifsud, S; Di Rago, L; Metcalft, D; Ernst, M; Dewson, G; Roberts, AW; Alexander, WS; Murphy, JM; Ekert, PG; Masters, SL; Vaux, DL; Croker, BA; Gerlic, M; Silke, J

Author(s): Rickard, JA; O'Donnell, JA; Evans, JM; Lalaoui, N; Poh, AR; Rogers, T; Vince, JE; Lawlor, KE; Ninnis, RL; Anderton, H; Hall, CJ; Spall, SK; Phesse, TJ; Abud, HE; Cengia, LH; Corbin, J; Mifsud, S; Di Rago, L; Metcalft, D; Ernst, M; Dewson, G; Roberts, AW; Alexander, WS; Murphy, JM; Ekert, PG; Masters, SL; Vaux, DL; Croker, BA; Gerlic, M; Silke, J;
Details: Publication Year 2014-05-07,Volume 157,Issue #5,Page 1175-88
Journal Title: Cell
Publication Type: Journal Article
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.
Publisher: Cell Press
Research Division(s): Cell Signalling And Cell Death; Cancer And Haematology; Inflammation
Publisher's Version: https://doi.org/10.1016/j.cell.2014.04.019.
NHMRC Grants: NHMRC/1016647, NHMRC/461221, NHMRC/1016701, NHMRC/1025594, NHMRC/1046984, NHMRC/1046010, NHMRC/1025239, NHMRC/637367, NHMRC/1008131,

Creation Date: 2014-05-12 05:05:32

Last Modified: 2015-09-07 10:29:37