| Literature DB >> 31819256 |
Mary Speir1,2,3,4, Cameron J Nowell5, Alyce A Chen1,2, Joanne A O'Donnell6,7, Isaac S Shamie8, Paul R Lakin9, Akshay A D'Cruz1,2, Roman O Braun1,2, Jeff J Babon6,7, Rowena S Lewis6,7, Meghan Bliss-Moreau1,2, Inbar Shlomovitz10, Shu Wang1,2, Louise H Cengia6, Anca I Stoica1, Razq Hakem11, Michelle A Kelliher12, Lorraine A O'Reilly6,7, Heather Patsiouras13, Kate E Lawlor3,4, Edie Weller1,9, Nathan E Lewis8,14,15, Andrew W Roberts6,7, Motti Gerlic10, Ben A Croker16,17,18,19,20.
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.Entities:
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Year: 2019 PMID： 31819256 PMCID： PMC6923591 DOI： 10.1038/s41590-019-0550-7
Source DB: PubMed Journal: Nat Immunol ISSN： 1529-2908 Impact factor: 25.606