RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis

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

doi:10.1016/j.cell.2014.04.019

RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis

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 ErnstGrant 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

^*Corresponding author for this work

Clinical Microbiology and Immunology

Research output: Contribution to journal › Article › peer-review

511 Scopus citations

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.

Original language	English
Pages (from-to)	1175-1188
Number of pages	14
Journal	Cell
Volume	157
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2014.04.019
State	Published - 22 May 2014

Funding

Funders	Funder number
Australian Research Council
Operational Infrastructure Support
Veski
State Government of Victoria
Australian Cancer Research Foundation
La Trobe University
Dora Lush Scholarship
National Health and Medical Research Council	1057905, 1046984, 1025239, 461221, 541901, 1058344, 1016647, 1008131, 1016701, 637367, 361646, 1025594, 1046010
Cancer Council Tasmania	637309

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2014.04.019

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Rickard, J. A., O'Donnell, J. A., Evans, J. M., Lalaoui, N., Poh, A. R., Rogers, T., Vince, J. E., Lawlor, K. E., Ninnis, R. L., Anderton, H., Hall, C., Spall, S. K., Phesse, T. J., Abud, H. E., Cengia, L. H., Corbin, J., Mifsud, S., Di Rago, L., Metcalf, D., ... Silke, J. (2014). RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell, 157(5), 1175-1188. https://doi.org/10.1016/j.cell.2014.04.019

@article{3da87eb733fb4b25aad6177fc3c06cdf,

title = "RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis",

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.",

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

note = "Funding Information: We thank staff in the WEHI Bioservices facility, Vishva Dixit for Ripk3 −/− mice, Michelle Kelliher for Ripk1 −/− mice, Heinrich Korner for Tnf −/− and Tnfr1 −/− mice, Stephen Hedrick for Casp8 fl/fl 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). ",

year = "2014",

month = may,

day = "22",

doi = "10.1016/j.cell.2014.04.019",

language = "אנגלית",

volume = "157",

pages = "1175--1188",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "5",

}

Rickard, JA, O'Donnell, JA, Evans, JM, Lalaoui, N, Poh, AR, Rogers, T, Vince, JE, Lawlor, KE, Ninnis, RL, Anderton, H, Hall, C, Spall, SK, Phesse, TJ, Abud, HE, Cengia, LH, Corbin, J, Mifsud, S, Di Rago, L, Metcalf, D, Ernst, M, Dewson, G, Roberts, AW, Alexander, WS, Murphy, JM, Ekert, PG, Masters, SL, Vaux, DL, Croker, BA, Gerlic, M & Silke, J 2014, 'RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis', Cell, vol. 157, no. 5, pp. 1175-1188. https://doi.org/10.1016/j.cell.2014.04.019

TY - JOUR

T1 - RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis

AU - Rickard, James A.

AU - O'Donnell, Joanne A.

AU - Evans, Joseph M.

AU - Lalaoui, Najoua

AU - Poh, Ashleigh R.

AU - Rogers, Tewhiti

AU - Vince, James E.

AU - Lawlor, Kate E.

AU - Ninnis, Robert L.

AU - Anderton, Holly

AU - Hall, Cathrine

AU - Spall, Sukhdeep K.

AU - Phesse, Toby J.

AU - Abud, Helen E.

AU - Cengia, Louise H.

AU - Corbin, Jason

AU - Mifsud, Sandra

AU - Di Rago, Ladina

AU - Metcalf, Donald

AU - Ernst, Matthias

AU - Dewson, Grant

AU - Roberts, Andrew W.

AU - Alexander, Warren S.

AU - Murphy, James M.

AU - Ekert, Paul G.

AU - Masters, Seth L.

AU - Vaux, David L.

AU - Croker, Ben A.

AU - Gerlic, Motti

AU - Silke, John

N1 - Funding Information: We thank staff in the WEHI Bioservices facility, Vishva Dixit for Ripk3 −/− mice, Michelle Kelliher for Ripk1 −/− mice, Heinrich Korner for Tnf −/− and Tnfr1 −/− mice, Stephen Hedrick for Casp8 fl/fl 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).

PY - 2014/5/22

Y1 - 2014/5/22

N2 - 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.

AB - 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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U2 - 10.1016/j.cell.2014.04.019

DO - 10.1016/j.cell.2014.04.019

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C2 - 24813849

AN - SCOPUS:84901422731

SN - 0092-8674

VL - 157

SP - 1175

EP - 1188

JO - Cell

JF - Cell

IS - 5

ER -

RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis

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