RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD.
RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD.
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RIPK3-MLKL 介导的坏死性炎症有助于 AKI 进展为 CKD
DOI：
10.1038/s41419-018-0936-8
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发表时间：
2018-08-29
影响因子：
9
通讯作者：
Xu Y
中科院分区：
文献类型：
--
作者：
Chen H;Fang Y;Wu J;Chen H;Zou Z;Zhang X;Shao J;Xu Y
在肾缺血再灌注损伤（IRI）的病理生理学中，坏死在功能上优于凋亡。抑制坏死性凋亡途径受体相互作用蛋白激酶1（RIPK 1）、RIPK 3或混合谱系激酶结构域样蛋白（MLKL）的核心组分可减少缺血/再灌注（IR）后的肾损伤。坏死可以引发炎症，这在正反馈回路中增强坏死，随后导致触发更多的炎症，称为坏死性炎症。然而，在阿基进展为CKD过程中，由肾小管细胞坏死性凋亡驱动的坏死性炎症的潜在机制仍然很大程度上未知。在此，我们发现RIPK 3和MLKL之间的上调表达和相互作用诱导了肾近端小管细胞的坏死性凋亡，并有助于在IRI条件下NLRP 3炎性小体的激活。Ripk 3或Mlkl基因缺失可改善肾小管细胞坏死性凋亡、巨噬细胞浸润和NLRP 3炎性小体激活，减少半胱氨酸蛋白酶-1激活和IL-1β成熟，最终减少IRI后长期间质纤维化。骨髓嵌合体证实，RIPK 3-MLKL依赖性坏死性凋亡是IRI后早期肾损伤开始的原因，然后坏死性凋亡触发NLRP 3炎性小体激活，随后加速坏死性凋亡并在自动放大环中触发更多炎症。这些数据表明，由RIPK 3-MLKL依赖性坏死性凋亡驱动的坏死性炎症在IRI进展为CKD中起着至关重要的作用。
Necroptosis predominates functionally over apoptosis in the pathophysiology of renal ischemia-reperfusion injury (IRI). Inhibition of the core components of the necroptotic pathway—receptor-interacting protein kinase 1 (RIPK1), RIPK3 or mixed lineage kinase domain-like protein (MLKL) reduced renal injury after ischemia/reperfusion (IR). Necrosis can initiate inflammation, which enhances necrosis in a positive feedback loop, subsequently leading to triggering more inflammation, termed as necroinflammation. However, the mechanisms underlying necroinflammation driven by renal tubular cell necroptosis in progression of AKI to CKD are still largely unknown. Here we showed that the upregulated expression and interactions between RIPK3 and MLKL induced necroptosis of renal proximal tubular cells and contributed to NLRP3 inflammasome activation under the conditions of IRI. Gene deletion of Ripk3 or Mlkl ameliorated renal tubular cell necroptosis, macrophage infiltration and NLRP3 inflammasome activation with a reduction in caspase-1 activation and maturation of IL-1β, and then finally reduced interstitial fibrogenesis in the long term after IRI. Bone marrow chimeras confirmed that RIPK3-MLKL-dependent necroptosis is responsible for the initiation of the early renal injury after IRI, and then necroptosis triggered NLRP3 inflammasome activation, which subsequently accelerates necroptosis and triggers more inflammation in an auto-amplification loop. These data indicate that necroinflammation driven by RIPK3-MLKL-dependent necroptosis plays a crucial role in the progression of IRI to CKD.
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RIP1-RIP3异源相互作用和RIP3-RIP3同源相互作用在介导坏死性凋亡中的不同作用
影响因子：
12.4
作者：
Wu, X-N;Yang, Z-H;Han, J.
通讯作者：
Han, J.
影响因子：
64.8
作者：
Oberst, Andrew;Dillon, Christopher P.;Weinlich, Ricardo;McCormick, Laura L.;Fitzgerald, Patrick;Pop, Cristina;Hakem, Razq;Salvesen, Guy S.;Green, Douglas R.
通讯作者：
Green, Douglas R.
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DOI：
10.1073/pnas.1716959115
发表时间：
2018-02-13
影响因子：
11.1
作者：
Liu, Wenjing;Chen, Binbin;Xia, Yin
通讯作者：
Xia, Yin
影响因子：
32.4
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
通讯作者：
Wallach, David
影响因子：
19.6
作者：
Linkermann, Andreas;Braesen, Jan H.;Krautwald, Stefan
通讯作者：
Krautwald, Stefan