RIPK1 regulates RIPK3-MLKL driven systemic inflammation and emergency hematopoiesis.
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
WEHI Research Division(s)
Cell Signalling And Cell Death; Cancer And Haematology; Inflammation
Rights Notice
Copyright © 2014 Elsevier Inc. All rights reserved.


Creation Date: 2014-05-12 05:05:32
Last Modified: 2015-09-07 10:29:37
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