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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. © 2014 Elsevier Inc.

Original publication

DOI

10.1016/j.cell.2014.04.019

Type

Journal article

Journal

Cell

Publication Date

22/05/2014

Volume

157

Pages

1175 - 1188