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

doi:10.1038/s41590-019-0550-7

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

Nat Immunol. 2020 Jan;21(1):54-64. doi: 10.1038/s41590-019-0550-7. Epub 2019 Dec 9.

Authors

Mary Speir^{1

2

3

4}, Cameron J Nowell⁵, Alyce A Chen^{1

2}, Joanne A O'Donnell^{6

7}, Isaac S Shamie⁸, Paul R Lakin⁹, Akshay A D'Cruz^{1

2}, Roman O Braun^{1

2}, Jeff J Babon^{6

7}, Rowena S Lewis^{6

7}, Meghan Bliss-Moreau^{1

2}, Inbar Shlomovitz¹⁰, Shu Wang^{1

2}, Louise H Cengia⁶, Anca I Stoica¹, Razq Hakem¹¹, Michelle A Kelliher¹², Lorraine A O'Reilly^{6

7}, Heather Patsiouras¹³, Kate E Lawlor^{3

4}, Edie Weller^{1

9}, Nathan E Lewis^{8

14

15}, Andrew W Roberts^{6

7}, Motti Gerlic¹⁰, Ben A Croker^{16

17

18

19

20}

Affiliations

¹ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
² Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
³ Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.
⁴ Department of Molecular and Translational Science, Monash University, Melbourne, Victoria, Australia.
⁵ Monash Institute of Pharmaceutical Sciences, Melbourne, Victoria, Australia.
⁶ Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
⁷ Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
⁹ Biostatistics and Research Design Center, Institutional Centers for Clinical and Translational Research, Boston Children's Hospital, Boston, MA, USA.
¹⁰ Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹¹ Princess Margaret Cancer Centre/University Health Network, University of Toronto, Toronto, Canada.
¹² Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
¹³ Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Melbourne, Victoria, Australia.
¹⁴ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
¹⁵ Novo Nordisk Foundation Center for Biosustainability, University of California San Diego, La Jolla, CA, USA.
¹⁶ Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. [email protected].
¹⁷ Department of Pediatrics, Harvard Medical School, Boston, MA, USA. [email protected].
¹⁸ Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. [email protected].
¹⁹ Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. [email protected].
²⁰ Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. [email protected].

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 neutrophils displayed increased p38 mitogen-activated protein kinase-dependent Ripk1-independent IL-1 and tumor necrosis factor production, and were prone to cell death. Together, these data emphasize dual functions for Ptpn6 in the negative regulation of p38 mitogen-activated protein kinase activation to control tumor necrosis factor and IL-1α/β expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1α/β release.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Apoptosis / immunology*
Caspase 8 / genetics
Caspase 8 / immunology*
Cells, Cultured
Gene Deletion
Inflammation / immunology
Interleukin-1 / immunology
Interleukin-1alpha / metabolism
Interleukin-1beta / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophils / immunology*
Protein Kinases / immunology*
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism*
Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
Receptors, Interleukin-1 Type I / immunology
Tumor Necrosis Factor-alpha / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism

Substances

IL1B protein, mouse
IL1R1 protein, mouse
Interleukin-1
Interleukin-1alpha
Interleukin-1beta
Receptors, Interleukin-1 Type I
Tumor Necrosis Factor-alpha
MLKL protein, mouse
Protein Kinases
Receptor-Interacting Protein Serine-Threonine Kinases
Ripk1 protein, mouse
Ripk3 protein, mouse
p38 Mitogen-Activated Protein Kinases
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Ptpn6 protein, mouse
Caspase 8

Abstract

Publication types

MeSH terms

Substances

Grants and funding