Ptpn6 inhibits caspase-8-and Ripk3/Mlkl-dependent inflammation

Mary Speir; Cameron J Nowell; Alyce A Chen; Joanne A O'Donnell; Isaac S Shamie; Paul R Lakin; Akshay A D'Cruz; Roman O Braun; Jeff J Babon; Rowena S Lewis; Meghan Bliss-Moreau; Inbar Shlomovitz; Shu Wang; Louise H Cengia; Anca I Stoica; Razq Hakem; Michelle A Kelliher; Lorraine A O'Reilly; Heather Patsiouras; Kate E Lawlor; Edie Weller; Nathan E Lewis; Andrew W Roberts; Motti Gerlic; Ben A Croker

Journal article

Ptpn6 inhibits caspase-8-and Ripk3/Mlkl-dependent inflammation

Mary Speir, Cameron J Nowell, Alyce A Chen, Joanne A O'Donnell, Isaac S Shamie, Paul R Lakin, Akshay A D'Cruz, Roman O Braun, Jeff J Babon, Rowena S Lewis, Meghan Bliss-Moreau, Inbar Shlomovitz, Shu Wang, Louise H Cengia, Anca I Stoica, Razq Hakem, Michelle A Kelliher, Lorraine A O'Reilly, Heather Patsiouras, Kate E Lawlor Show all

Nature Immunology | NATURE PUBLISHING GROUP | Published : 2020

DOI: 10.1038/s41590-019-0550-7

Abstract

Ptpn6 is a cytoplasmic phosphatase that functions to prevent autoimmune and interleukin-1 (IL-1) receptor-dependent, caspase-1-independent inflammatory disease. Conditional deletion of Ptpn6 in neutrophils (Ptpn6∆PMN) is sufficient to initiate IL-1 receptor-dependent cutaneous inflammatory disease, but the source of IL-1 and the mechanisms behind IL-1 release remain unclear. Here, we investigate the mechanisms controlling IL-1α/β release from neutrophils by inhibiting caspase-8-dependent apoptosis and Ripk1-Ripk3-Mlkl-regulated necroptosis. Loss of Ripk1 accelerated disease onset, whereas combined deletion of caspase-8 and either Ripk3 or Mlkl strongly protected Ptpn6∆PMN mice. Ptpn6∆PMN neu..

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University of Melbourne Researchers

Kate Lawlor Author Medical Biology (W.E.H.I.)

Jeffrey Babon Author Medical Biology (W.E.H.I.)

Lorraine O'Reilly Author Medical Biology (W.E.H.I.)

Andrew Roberts Author

Grants

Awarded by NIH/AID

Awarded by NIH

Awarded by ISF

Awarded by Alpha-1 Foundation

Awarded by United States-Israel Binational Science Foundation

Awarded by NHMRC

Awarded by NHMRC Independent Research Institutes Infrastructure Support Scheme grant

Awarded by Novo Nordisk Foundation

Awarded by NIGMS

Funding Acknowledgements

Mlkl-/- mice were provided by W. S. Alexander (Walter and Eliza Hall Institute of Medical Research). Ripk3-/- mice were provided by V. Dixit (Genentech). Ripk1-/-, conditional Ripk1fl/fl and Ripk1D138N mice were provided by M. Kelliher and M. Pasparakis, supported by NIH/AID grant RO1 AI075118. Casp8 antibody was provided by A. Strasser (Walter and Eliza Hall Institute of Medical Research). This work was supported by NIH grant 5RO1HL124209 (to B.A.C.), the American Asthma Foundation (to B.A.C.), ISF grants 1416/15 and 818/18 (to M.G.), Alpha-1 Foundation grant 615533 (to M.G.), the Recanati Foundation and Varda and Boaz Dotan Research Center (to M.G.), United States-Israel Binational Science Foundation grant 2017176 (to M.G. and B.A.C.), the Australian National Health and Medical Research Council (NHMRC) Dora Lush Scholarship (to J.A.O.) and NHMRC grants 637367, 1145788 and 1162765. This work was supported by a NHMRC Independent Research Institutes Infrastructure Support Scheme grant (9000220), and a Victorian State Government Operational Infrastructure Support grant, support from the Novo Nordisk Foundation provided to the Center for Biosustainability at the Technical University of Denmark (NNF10CC1016517 to N.E.L.) and NIGMS (R35 GM119850 to I.S.). Live-cell imaging performed at Boston Children's Hospital Intellectual Developmental Disabilities Research Center is supported by grant 1U54HD0902565.