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 E Corbin; Sandra Mifsud; Ladina Di Rago; Donald Metcalf; Matthias R 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 E Corbin, Sandra Mifsud, Ladina Di Rago, Donald Metcalf, Matthias R 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

Anatomy & Developmental Biology

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

485 Citations (Scopus)

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
Publication status	Published - 2014

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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. E., 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{5fdebd714e5e4ba5ad400d45c27f9a94,

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 Corbin, {Jason E} and Sandra Mifsud and {Di Rago}, Ladina and Donald Metcalf and Ernst, {Matthias R} 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",

year = "2014",

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

language = "English",

volume = "157",

pages = "1175 -- 1188",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

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, JE, Mifsud, S, Di Rago, L, Metcalf, D, Ernst, MR, 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 E

AU - Mifsud, Sandra

AU - Di Rago, Ladina

AU - Metcalf, Donald

AU - Ernst, Matthias R

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

PY - 2014

Y1 - 2014

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.

UR - http://www.sciencedirect.com/science/article/pii/S0092867414005376

U2 - 10.1016/j.cell.2014.04.019

DO - 10.1016/j.cell.2014.04.019

M3 - Article

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

Abstract

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