Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis.
Cytotoxicity of crystals involves RIPK3-MLKL-mediated necroptosis.
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DOI：
10.1038/ncomms10274
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发表时间：
2016-01-28
影响因子：
16.6
通讯作者：
Anders HJ
中科院分区：
文献类型：
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作者：
Mulay SR;Desai J;Kumar SV;Eberhard JN;Thomasova D;Romoli S;Grigorescu M;Kulkarni OP;Popper B;Vielhauer V;Zuchtriegel G;Reichel C;Bräsen JH;Romagnani P;Bilyy R;Munoz LE;Herrmann M;Liapis H;Krautwald S;Linkermann A;Anders HJ
晶体在许多疾病中引起损伤，并通过NLRP 3炎性体诱导炎症，然而，晶体如何诱导细胞死亡仍不清楚。在这里，我们报告了草酸钙，草酸钙，焦磷酸钙二水合物和胱氨酸晶体触发半胱天冬酶非依赖性细胞死亡在五种不同的细胞类型，这是由necrostatin-1阻断。针对受体相互作用蛋白激酶3（RIPK 3）或混合谱系激酶结构域样（MLKL）（坏死性凋亡途径的两种核心蛋白）的RNA干扰阻断晶体细胞毒性。与此一致，RIPK 3或MLKL的缺乏可预防草酸盐晶体诱导的急性肾损伤。相关的组织炎症驱动TNF-α相关的坏死性凋亡。同样在人草酸盐晶体相关急性肾损伤中，垂死的肾小管细胞对磷酸化MLKL染色呈阳性。此外，necrostatin-1和necrosulfonamide（一种人MLKL抑制剂）可抑制人肾祖细胞中晶体诱导的细胞死亡。总之，TNF-α/TNFR 1、RIPK 1、RIPK 3和MLKL是限制晶体诱导的细胞毒性、组织损伤和器官衰竭的分子靶点。 肾结石是由草酸盐晶体的积累引起的，草酸盐晶体会引发组织损伤、炎症和细胞死亡。Mulay等人表明晶体通过坏死性凋亡诱导肾脏中的细胞死亡，并提出该途径可能是治疗晶体诱导疾病的靶点。
Crystals cause injury in numerous disorders, and induce inflammation via the NLRP3 inflammasome, however, it remains unclear how crystals induce cell death. Here we report that crystals of calcium oxalate, monosodium urate, calcium pyrophosphate dihydrate and cystine trigger caspase-independent cell death in five different cell types, which is blocked by necrostatin-1. RNA interference for receptor-interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain like (MLKL), two core proteins of the necroptosis pathway, blocks crystal cytotoxicity. Consistent with this, deficiency of RIPK3 or MLKL prevents oxalate crystal-induced acute kidney injury. The related tissue inflammation drives TNF-α-related necroptosis. Also in human oxalate crystal-related acute kidney injury, dying tubular cells stain positive for phosphorylated MLKL. Furthermore, necrostatin-1 and necrosulfonamide, an inhibitor for human MLKL suppress crystal-induced cell death in human renal progenitor cells. Together, TNF-α/TNFR1, RIPK1, RIPK3 and MLKL are molecular targets to limit crystal-induced cytotoxicity, tissue injury and organ failure. Kidney stone disease is caused by accumulation of oxalate crystals, which trigger tissue injury, inflammation and cell death. Mulay et al. show that crystals induce cell death in the kidney through necroptosis, and propose that this pathway may be a target for the treatment of crystal-induced disease.