期刊
NATURE IMMUNOLOGY
卷 21, 期 1, 页码 54-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41590-019-0550-7
关键词
-
类别
资金
- NIH/AID [RO1 AI075118]
- NIH [5RO1HL124209]
- American Asthma Foundation
- ISF [1416/15, 818/18]
- Alpha-1 Foundation [615533]
- Recanati Foundation
- Varda and Boaz Dotan Research Center
- United States-Israel Binational Science Foundation [2017176]
- Australian National Health and Medical Research Council (NHMRC) Dora Lush Scholarship
- NHMRC [637367, 1145788, 1162765]
- NHMRC Independent Research Institutes Infrastructure Support Scheme grant [9000220]
- Victorian State Government Operational Infrastructure Support grant
- Novo Nordisk Foundation [NNF10CC1016517]
- NIGMS [R35 GM119850]
- [1U54HD0902565]
- National Health and Medical Research Council of Australia [1145788, 1162765] Funding Source: NHMRC
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(Delta 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-1 alpha/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(Delta PMN) mice. Ptpn6(Delta 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-1 alpha/beta expression, and in maintaining Ripk1 function to prevent caspase-8- and Ripk3-Mlkl-dependent cell death and concomitant IL-1 alpha/beta release.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据