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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.date.accessioned2020-12-14T05:41:44Z
dc.date.available2020-12-14T05:41:44Z
dc.date.issued2020-01-01
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-+. https://doi.org/10.1038/s41590-019-0550-7.
dc.identifier.issn1529-2908
dc.identifier.urihttp://hdl.handle.net/11343/253978
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.languageEnglish
dc.publisherNATURE PUBLISHING GROUP
dc.titlePtpn6 inhibits caspase-8-and Ripk3/Mlkl-dependent inflammation
dc.typeJournal Article
dc.identifier.doi10.1038/s41590-019-0550-7
melbourne.affiliation.departmentMedical Biology (W.E.H.I.)
melbourne.affiliation.departmentCentre for Cancer Research
melbourne.source.titleNature Immunology
melbourne.source.volume21
melbourne.source.issue1
melbourne.source.pages54-+
melbourne.elementsid1425954
melbourne.openaccess.urlhttp://europepmc.org/articles/pmc6923591?pdf=render
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
dc.identifier.eissn1529-2916
melbourne.accessrightsAccess this item via the Open Access location


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