Journal article
RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis
JA Rickard, JA O'Donnell, JM Evans, N Lalaoui, AR Poh, T Rogers, JE Vince, KE Lawlor, RL Ninnis, H Anderton, C Hall, SK Spall, TJ Phesse, HE Abud, LH Cengia, J Corbin, S Mifsud, L Di Rago, D Metcalf, M Ernst Show all
Cell | Published : 2014
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..
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Awarded by Australian Research Council
Funding Acknowledgements
We thank staff in the WEHI Bioservices facility, Vishva Dixit for Ripk3<SUP>-/-</SUP> mice, Michelle Kelliher for Ripk1<SUP>-/-</SUP> mice, Heinrich Korner for Tnf<SUP>-/-</SUP> and Tnfr1<SUP>-/-</SUP> mice, Stephen Hedrick for Casp8<SUP>fl/fl</SUP> mice, and Anne Voss for helpful discussions. This work was supported by NHMRC grants (1016647, 461221, 1016701, 1025594, 1046984, 1046010, 1025239, 637367, 1008131, and 1057905), an Australian Research Council Fellowship (B.A.C.), an APA scholarship (J.A.R.), a Dora Lush Scholarship (J.A.O.), a La Trobe University Postgraduate Research Scholarship (J.M. E.), a VESKI innovation fellowship (S.L.M.), ARC Fellowship (J.M. M.), Cancer Council Victoria Carden Fellowship (D.M.), and NHMRC fellowships to J.S., W.S.A., and A.W.R. (541901, 1058344, and 637309) with additional support from the Australian Cancer Research Fund, Victorian State Government Operational Infrastructure Support, and an NHMRC IRIISS grant (361646).