Journal
CELL
Volume 157, Issue 5, Pages 1175-1188Publisher
CELL PRESS
DOI: 10.1016/j.cell.2014.04.019
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Funding
- NHMRC [1016647, 461221, 1016701, 1025594, 1046984, 1046010, 1025239, 637367, 1008131, 1057905]
- Australian Research Council Fellowship
- APA scholarship
- Dora Lush Scholarship
- La Trobe University Postgraduate Research Scholarship
- VESKI innovation fellowship
- ARC Fellowship
- Cancer Council Victoria Carden Fellowship
- NHMRC fellowships [541901, 1058344, 637309]
- Australian Cancer Research Fund, Victorian State Government Operational Infrastructure Support
- NHMRC IRIISS grant [361646]
- National Health and Medical Research Council of Australia [1057905] Funding Source: NHMRC
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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.
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