1. RIPK1 Regulates RIPK3-MLKL-Driven Systemic Inflammation and Emergency Hematopoiesis
- Author
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TeWhiti Rogers, Warren S. Alexander, Motti Gerlic, Donald Metcalf, Paul G Ekert, Ladina Di Rago, Grant Dewson, Seth L. Masters, Toby J. Phesse, Jason Corbin, Andrew W. Roberts, James A Rickard, Sandra Mifsud, Ashleigh R Poh, Robert L Ninnis, Louise H. Cengia, Sukhdeep K Spall, James E Vince, Cathrine Hall, Holly Anderton, Kate E. Lawlor, Matthias Ernst, Najoua Lalaoui, Joanne A. O’Donnell, Ben A. Croker, James M. Murphy, Joseph M Evans, David L. Vaux, Helen E. Abud, and John Silke
- Subjects
Programmed cell death ,Mice, 129 Strain ,Necroptosis ,Inflammation ,Biology ,Systemic inflammation ,Caspase 8 ,General Biochemistry, Genetics and Molecular Biology ,RIPK1 ,Mice ,medicine ,Animals ,Receptor ,Cell Death ,Biochemistry, Genetics and Molecular Biology(all) ,3. Good health ,Hematopoiesis ,Mice, Inbred C57BL ,Animals, Newborn ,Liver ,Receptors, Tumor Necrosis Factor, Type I ,Receptor-Interacting Protein Serine-Threonine Kinases ,Myeloid Differentiation Factor 88 ,Tumor Necrosis Factors ,Cancer research ,Tumor necrosis factor alpha ,Genes, Lethal ,medicine.symptom ,Protein Kinases - 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.
- Published
- 2014
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