Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis
Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis
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DOI：
10.1073/pnas.1708247114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Kettritz, Ralph
中科院分区：
文献类型：
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作者：
Schreiber, Adrian;Rousselle, Anthony;Kettritz, Ralph
抗中性粒细胞胞浆抗体 (ANCA) 相关血管炎 (AAV) 是一种危及生命的自身免疫性疾病，影响每个器官，包括肾脏，并导致坏死性新月体肾小球肾炎。 ANCA 激活中性粒细胞，激活的中性粒细胞会损伤内皮，导致血管炎症和坏死。更好地了解中性粒细胞介导的 AAV 疾病机制可能会揭示新的治疗策略。在此，我们报告 ANCA 通过受体相互作用蛋白激酶 (RIPK) 1/3 和混合谱系激酶结构域样 (MLKL) 依赖性坏死性凋亡诱导中性粒细胞胞外陷阱 (NET)。 ANCA 刺激的中性粒细胞产生的 NET 在体外引起内皮细胞 (EC) 损伤。这种效应可以通过 (i) RIPK1 的药理学抑制或 (ii) 酶促 NET 降解来阻止。最近，AAV 涉及替代补体途径 (AP)，而 C5a 抑制目前正在临床研究中进行测试。我们观察到 NET 为 AP 激活提供了支架，进而导致 EC 损伤。我们进一步确定了 NET 的体内相关性以及 RIPK1/3/MLKL 依赖性坏死性凋亡的要求，特别是在骨髓源性隔室中，使用鼠 AAV 模型和人肾活检进行疾病诱导。总之，我们确定了 ANCA 诱导的中性粒细胞激活、坏死性凋亡、NET、AP 和内皮损伤之间的机制联系。 RIPK1 抑制剂目前正在临床试验中进行评估，并在 AAV 中展现出一种新颖的治疗策略。
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes life-threatening autoimmune diseases affecting every organ, including the kidneys, where they cause necrotizing crescentic glomerulonephritis. ANCA activates neutrophils and activated neutrophils damage the endothelium, leading to vascular inflammation and necrosis. Better understanding of neutrophilmediated AAV disease mechanisms may reveal novel treatment strategies. Here we report that ANCA induces neutrophil extracellular traps (NETs) via receptor-interacting protein kinase (RIPK) 1/3-and mixed-lineage kinase domain-like (MLKL)-dependent necroptosis. NETs from ANCA-stimulated neutrophils caused endothelial cell (EC) damage in vitro. This effect was prevented by (i) pharmacologic inhibition of RIPK1 or (ii) enzymatic NET degradation. The alternative complement pathway (AP) was recently implicated in AAV, and C5a inhibition is currently being tested in clinical studies. We observed that NETs provided a scaffold for AP activation that in turn contributed to EC damage. We further established the in vivo relevance of NETs and the requirement of RIPK1/3/MLKL-dependent necroptosis, specifically in the bone marrow-derived compartment, for disease induction using murine AAV models and in human kidney biopsies. In summary, we identified a mechanistic link between ANCA-induced neutrophil activation, necroptosis, NETs, the AP, and endothelial damage. RIPK1 inhibitors are currently being evaluated in clinical trials and exhibit a novel therapeutic strategy in AAV.