RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis | Zendy

James A. Rickard | Zendy; Joanne A. O’Donnell | Zendy; Joseph M. Evans | Zendy; Najoua Lalaoui | Zendy; Ashleigh R. Poh | Zendy; TeWhiti Rogers | Zendy; James E. Vince | Zendy; Kate E. Lawlor | Zendy; Robert L. Ninnis | Zendy; Holly Anderton | Zendy; Cathrine Hall | Zendy; Sukhdeep K. Spall | Zendy; Toby J. Phesse | Zendy; Helen E. Abud | Zendy; Louise H. Cengia | Zendy; Jason Corbin | Zendy; Sandra Mifsud | Zendy; Ladina Di Rago | Zendy; Donald Metcalf | Zendy; Matthias Ernst | Zendy; Grant Dewson | Zendy; Andrew W. Roberts | Zendy; Warren S. Alexander | Zendy; James M. Murphy | Zendy; Paul G. Ekert | Zendy; Seth L. Masters | Zendy; David L. Vaux | Zendy; Ben A. Croker | Zendy; Motti Gerlic | Zendy; John Silke | Zendy

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RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis

Author(s) -

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 Corbin,

Sandra Mifsud,

Ladina Di Rago,

Donald Metcalf,

Matthias Ernst,

Grant 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

Publication year - 2014

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2014.04.019

Subject(s) - biology , inflammation , haematopoiesis , microbiology and biotechnology , ripk1 , systemic inflammation , cancer research , programmed cell death , immunology , necroptosis , apoptosis , genetics , stem cell

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.

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