| Literature DB >> 24813849 |
James A Rickard1, Joanne A O'Donnell1, Joseph M Evans2, Najoua Lalaoui1, Ashleigh R Poh1, TeWhiti Rogers3, James E Vince1, Kate E Lawlor1, Robert L Ninnis1, Holly Anderton1, Cathrine Hall1, Sukhdeep K Spall1, Toby J Phesse1, Helen E Abud4, Louise H Cengia1, Jason Corbin1, Sandra Mifsud1, Ladina Di Rago1, Donald Metcalf1, Matthias Ernst1, Grant Dewson1, Andrew W Roberts5, Warren S Alexander1, James M Murphy1, Paul G Ekert1, Seth L Masters1, David L Vaux1, Ben A Croker6, Motti Gerlic7, John Silke8.
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.Entities:
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Year: 2014 PMID： 24813849 DOI： 10.1016/j.cell.2014.04.019
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582