Ptpn6抑制caspase-8和Ripk3/Mlkl依賴性炎症

Ptpn6抑制caspase-8和Ripk3/Mlkl依賴性炎症

作者：

小柯機器人

發布時間：2019/12/10 14:49:07

美國波士頓兒童醫院Ben A. Croker研究組最新研究發現，Ptpn6（胞質磷酸酶）抑制caspase-8-和Ripk3/ Mlkl依賴性的炎症。這一研究成果在線發表在2019年12月9日的國際學術期刊《自然—免疫學》上。

研究人員通過抑制caspase-8依賴性的凋亡和Ripk1–Ripk3–Mlkl調控的壞死，研究了控制白介素1（IL-1）α/β從中性粒細胞中釋放的機制。Ripk1的缺失加速了疾病的進展，而caspase-8和Ripk3或Mlk1的組合缺失則可以顯著保護Ptpn6ΔPMN（中性粒細胞中Ptpn6的條件缺失小鼠）。 Ptpn6^ΔPMN中性粒細胞具有增強的p38絲裂原活化蛋白激酶依賴而Ripk1非依賴的IL-1和腫瘤壞死因子的產生，並易於發生細胞死亡。這些結果揭示了Ptpn6的雙重功能，即通過負調控p38絲裂原活化蛋白激酶的激活，來控制腫瘤壞死因子和IL-1α/β的表達，並維持Ripk1的功能以阻止caspase-8-和Ripk3-Mlkl-依賴的細胞死亡和與之伴隨的IL-1α/β釋放。

據了解，Ptpn6是一種胞質磷酸酶，其功能是預防自身免疫和IL-1受體依賴性而caspase-1非依賴性的炎性疾病。中性粒細胞中Ptpn6的條件缺失（Ptpn6^ΔPMN）足以引起IL-1受體依賴性皮膚炎，但尚不清楚IL-1的來源和IL-1釋放的機制。

附：英文原文

Title: Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation

Author: Mary Speir, Cameron J. Nowell, Alyce A. Chen, Joanne A. ODonnell, Isaac S. Shamie, Paul R. Lakin, Akshay A. DCruz, Roman O. Braun, Jeff J. Babon, Rowena S. Lewis, Meghan Bliss-Moreau, Inbar Shlomovitz, Shu Wang, Louise H. Cengia, Anca I. Stoica, Razq Hakem, Michelle A. Kelliher, Lorraine A. OReilly, Heather Patsiouras, Kate E. Lawlor, Edie Weller, Nathan E. Lewis, Andrew W. Roberts, Motti Gerlic, Ben A. Croker

Issue&Volume: 2019-12-09

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 (Ptpn6PMN) 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 Ptpn6PMN mice. Ptpn6PMN 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.

DOI: 10.1038/s41590-019-0550-7

Source: https://www.nature.com/articles/s41590-019-0550-7