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dc.contributor.authorSpeir, M
dc.contributor.authorNowell, CJ
dc.contributor.authorChen, AA
dc.contributor.authorO'Donnell, JA
dc.contributor.authorShamie, IS
dc.contributor.authorLakin, PR
dc.contributor.authorD'Cruz, AA
dc.contributor.authorBraun, RO
dc.contributor.authorBabon, JJ
dc.contributor.authorLewis, RS
dc.contributor.authorBliss-Moreau, M
dc.contributor.authorShlomovitz, I
dc.contributor.authorWang, S
dc.contributor.authorCengia, LH
dc.contributor.authorStoica, AI
dc.contributor.authorHakem, R
dc.contributor.authorKelliher, MA
dc.contributor.authorO'Reilly, LA
dc.contributor.authorPatsiouras, H
dc.contributor.authorLawlor, KE
dc.contributor.authorWeller, E
dc.contributor.authorLewis, NE
dc.contributor.authorRoberts, AW
dc.contributor.authorGerlic, M
dc.contributor.authorCroker, BA
dc.identifierpii: 10.1038/s41590-019-0550-7
dc.identifier.citationSpeir, 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-+.
dc.description.abstractPtpn6 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.
dc.titlePtpn6 inhibits caspase-8-and Ripk3/Mlkl-dependent inflammation
dc.typeJournal Article
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentCentre for Cancer Research
melbourne.source.titleNature Immunology
melbourne.openaccess.statusAccepted version
melbourne.contributor.authorBabon, Jeffrey
melbourne.contributor.authorLawlor, Kathryn
melbourne.contributor.authorRoberts, Andrew
melbourne.contributor.authorO'Reilly, Lorraine
melbourne.contributor.authorO'Donnell, Joanne
melbourne.contributor.authorLEWIS, ROWENA
melbourne.accessrightsAccess this item via the Open Access location

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