Ptpn6 inhibits caspase-8-and Ripk3/Mlkl-dependent inflammation
Author
Speir, M; Nowell, CJ; Chen, AA; O'Donnell, JA; Shamie, IS; Lakin, PR; D'Cruz, AA; Braun, RO; Babon, JJ; Lewis, RS; ...Date
2020-01-01Source Title
Nature ImmunologyPublisher
NATURE PUBLISHING GROUPUniversity of Melbourne Author/s
Babon, Jeffrey; Lawlor, Kathryn; Roberts, Andrew; O'Reilly, Lorraine; O'Donnell, Joanne; LEWIS, ROWENAAffiliation
Medical Biology (W.E.H.I.)Centre for Cancer Research
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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
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http://europepmc.org/articles/pmc6923591?pdf=renderAbstract
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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