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

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

Author information

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. bcroker@health.ucsd.edu.
17
Department of Pediatrics, Harvard Medical School, Boston, MA, USA. bcroker@health.ucsd.edu.
18
Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia. bcroker@health.ucsd.edu.
19
Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia. bcroker@health.ucsd.edu.
20
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. bcroker@health.ucsd.edu.

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.

PMID:
31819256
PMCID:
PMC6923591
[Available on 2020-06-09]
DOI:
10.1038/s41590-019-0550-7

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