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Ptpn6抑制caspase-8和Ripk3/Mlkl依赖性炎症
2019-12-10 14:49

美国波士顿儿童医院Ben A. Croker研究组最新研究发现,Ptpn6(胞质磷酸酶)抑制caspase-8-和Ripk3/ Mlkl依赖性的炎症。这一研究成果在线发表在2019年12月9日的国际学术期刊《自然—免疫学》上。

研究人员通过抑制caspase-8依赖性的凋亡和Ripk1–Ripk3–Mlkl调控的坏死,研究了控制白介素1(IL-1)α/β从中性粒细胞中释放的机制。Ripk1的缺失加速了疾病的进展,而caspase-8和Ripk3或Mlk1的组合缺失则可以显著保护Ptpn6ΔPMN(中性粒细胞中Ptpn6的条件缺失小鼠)。 Ptpn6ΔPMN中性粒细胞具有增强的p38丝裂原活化蛋白激酶依赖而Ripk1非依赖的IL-1和肿瘤坏死因子的产生,并易于发生细胞死亡。这些结果揭示了Ptpn6的双重功能,即通过负调控p38丝裂原活化蛋白激酶的激活,来控制肿瘤坏死因子和IL-1α/β的表达,并维持Ripk1的功能以阻止caspase-8-和Ripk3-Mlkl-依赖的细胞死亡和与之伴随的IL-1α/β释放。

据了解,Ptpn6是一种胞质磷酸酶,其功能是预防自身免疫和IL-1受体依赖性而caspase-1非依赖性的炎性疾病。中性粒细胞中Ptpn6的条件缺失(Ptpn6ΔPMN)足以引起IL-1受体依赖性皮肤炎,但尚不清楚IL-1的来源和IL-1释放的机制。

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

Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:23.53
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex


本期文章:《自然—免疫学》:Online/在线发表

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