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

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    Author
    Speir, M; Nowell, CJ; Chen, AA; O'Donnell, JA; Shamie, IS; Lakin, PR; D'Cruz, AA; Braun, RO; Babon, JJ; Lewis, RS; ...
    Date
    2020-01-01
    Source Title
    Nature Immunology
    Publisher
    NATURE PUBLISHING GROUP
    University of Melbourne Author/s
    Babon, Jeffrey; Lawlor, Kathryn; Roberts, Andrew; O'Reilly, Lorraine; O'Donnell, Joanne; LEWIS, ROWENA
    Affiliation
    Medical Biology (W.E.H.I.)
    Centre for Cancer Research
    Metadata
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    Document Type
    Journal Article
    Citations
    Speir, M., Nowell, C. J., Chen, A. A., O'Donnell, J. A., Shamie, I. S., Lakin, P. R., D'Cruz, A. A., Braun, R. O., Babon, J. J., Lewis, R. S., Bliss-Moreau, M., Shlomovitz, I., Wang, S., Cengia, L. H., Stoica, A. I., Hakem, R., Kelliher, M. A., O'Reilly, L. A., Patsiouras, H. ,... Croker, B. A. (2020). Ptpn6 inhibits caspase-8-and Ripk3/Mlkl-dependent inflammation. NATURE IMMUNOLOGY, 21 (1), pp.54-+. https://doi.org/10.1038/s41590-019-0550-7.
    Access Status
    Access this item via the Open Access location
    URI
    http://hdl.handle.net/11343/253978
    DOI
    10.1038/s41590-019-0550-7
    Open Access URL
    http://europepmc.org/articles/pmc6923591?pdf=render
    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.

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