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

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 diseas...

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Published in:	Nature immunology Vol. 21; no. 1; pp. 54 - 64
Main Authors:	Speir, Mary, Nowell, Cameron J., Chen, Alyce A., O’Donnell, Joanne A., Shamie, Isaac S., Lakin, Paul R., D’Cruz, Akshay A., Braun, Roman O., Babon, Jeff J., Lewis, Rowena S., Bliss-Moreau, Meghan, Shlomovitz, Inbar, Wang, Shu, Cengia, Louise H., Stoica, Anca I., Hakem, Razq, Kelliher, Michelle A., O’Reilly, Lorraine A., Patsiouras, Heather, Lawlor, Kate E., Weller, Edie, Lewis, Nathan E., Roberts, Andrew W., Gerlic, Motti, Croker, Ben A.
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-01-2020 Nature Publishing Group
Subjects:	631/250/1932 631/250/2503 631/250/2504/223 631/250/256/2515 631/80/82/2344 Animals Apoptosis Apoptosis - immunology Biomedical and Life Sciences Biomedicine Caspase 8 - genetics Caspase 8 - immunology Caspase-8 Cell death Cells, Cultured Development and progression Gene Deletion Immunology Infectious Diseases Inflammation Inflammation - immunology Inflammatory diseases Interleukin 1 Interleukin-1 - immunology Interleukin-1alpha - metabolism Interleukin-1beta - metabolism Interleukins Kinases Mice Mice, Inbred C57BL Mice, Knockout Mitogens Necroptosis Neutrophils Neutrophils - immunology p38 Mitogen-Activated Protein Kinases - metabolism Phosphatases Protein kinases 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 Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-TNF Australia Fiji
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Summary:	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. Croker and colleagues show that the phosphatase Ptpn6 functions to suppress neutrophil cell death pathways and IL-1 release, thereby limiting autoinflammatory responses.
Bibliography:	Experiments: MS, AAC, JAO, AAD, ROB, JJB, RSL, MBM, IS, SW, LHC, AIS, HP, LAO, KEL, MG, BAC Funding: AWR, EW, NEL, KEL, RH, MAK, JJB, CJN, BAC Supervision: MS, AAC, JJB, EW, NEL, KEL, AWR, MG, BAC Project design: MS, AAC, JAO, AAD, JJB, RSL, MBM, IS, KEL, AIS, AWR, MG, BAC Software development: CJN Analysis: MS, CJN, AAC, JAO, ISS, PRL, AAD, ROB, JJB, RSL, MBM, IS, SW, LHC, AIS, HP, KEL, EW, NEL, AWR, MG, BAC Author Contributions Writing: MS, JAO, KEL, NEL, IS, MG, BAC
ISSN:	1529-2908 1529-2916
DOI:	10.1038/s41590-019-0550-7