Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation
- Author(s)
- Speir, M; Nowell, CJ; Chen, AA; O'Donnell, JA; Shamie, IS; Lakin, PR; D'Cruz, AA; Braun, RO; Babon, JJ; Lewis, RS; Bliss-Moreau, M; Shlomovitz, I; Wang, S; Cengia, LH; Stoica, AI; Hakem, R; Kelliher, MA; O'Reilly, LA; Patsiouras, H; Lawlor, KE; Weller, E; Lewis, NE; Roberts, AW; Gerlic, M; Croker, BA;
- Journal Title
- Nature Immunology
- Publication Type
- Journal Article in press
- 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-1alpha/beta 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-1alpha/beta expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1alpha/beta release.
- Publisher
- Springer Nature
- Research Division(s)
- Structural Biology; Inflammation; Blood Cells And Blood Cancer
- PubMed ID
- 31819256
- Publisher's Version
- https://doi.org/10.1038/s41590-019-0550-7
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2019-12-16 02:49:02
Last Modified: 2019-12-16 03:01:02