PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling
PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling
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DOI：
10.1002/eji.201545605
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发表时间：
2016-01-01
影响因子：
5.4
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Desai, Jyaysi;Kumar, Santhosh V.;Anders, Hans-Joachim
神经细胞外陷阱（NET）的形成有助于痛风，自身免疫性血管炎，血栓形成和动脉粥样硬化。触发NET形成的由外向内信号通路尚不清楚。在这里，我们表明，受体相互作用蛋白激酶（RIPK）-1-稳定剂necrostatin-1或necrostatin-1 s和混合谱系激酶结构域样（MLKL）抑制剂necrosulfonamide防止尿酸盐（MSU）晶体或PMA诱导的人类和小鼠中性粒细胞NET形成。这些化合物不影响PMA（-）或尿酸盐晶体诱导的ROS产生。此外，慢性肉芽肿病患者的中性粒细胞显示缺乏PMA诱导的MLKL磷酸化。小鼠中RIPK 3的遗传缺陷在体外和体内阻止MSU晶体诱导的NET形成。因此，中性粒细胞死亡和NET形成可能涉及ROS产生下游的坏死性凋亡的信号传导途径。这些数据意味着RIPK 1、RIPK 3和MLKL可能代表痛风或其他晶体病的分子靶点。
Neutrophil extracellular trap (NET) formation contributes to gout, autoimmune vasculitis, thrombosis, and atherosclerosis. The outside-in signaling pathway triggering NET formation is unknown. Here, we show that the receptor-interacting protein kinase (RIPK)-1-stabilizers necrostatin-1 or necrostatin-1s and the mixed lineage kinase domain-like (MLKL)-inhibitor necrosulfonamide prevent monosodium urate (MSU) crystal-or PMA-induced NET formation in human and mouse neutrophils. These compounds do not affect PMA(-) or urate crystal-induced production of ROS. Moreover, neutrophils of chronic granulomatous disease patients are shown to lack PMA-induced MLKL phosphorylation. Genetic deficiency of RIPK3 in mice prevents MSU crystal-induced NET formation in vitro and in vivo. Thus, neutrophil death and NET formation may involve the signaling pathway defining necroptosis downstream of ROS production. These data imply that RIPK1, RIPK3, and MLKL could represent molecular targets in gout or other crystallopathies.