Receptor interacting protein 3 kinase, not 1 kinase, through MLKL-mediated necroptosis is involved in UVA-induced corneal endothelium cell death.
Receptor interacting protein 3 kinase, not 1 kinase, through MLKL-mediated necroptosis is involved in UVA-induced corneal endothelium cell death.
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DOI：
10.1038/s41420-021-00757-w
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发表时间：
2021-11-23
影响因子：
7
通讯作者：
Vavvas DG
中科院分区：
文献类型：
--
作者：
Yu Z;Efstathiou NE;Correa VSMC;Chen X;Ishihara K;Iesato Y;Narimatsu T;Ntentakis D;Chen Y;Vavvas DG
紫外线（UV）是太阳光谱中能量最高的辐射之一，可导致各种组织损伤疾病。先前的研究表明，UVA（占入射光伏辐射的95%）诱导角膜内皮细胞（CEC）死亡。程序性细胞死亡（PCD）与许多眼科疾病有关。在这里，我们研究受体相互作用蛋白3激酶（RIPK 3），PCD的关键信号分子，在UVA诱导的损伤使用短期角膜内皮（CE）培养模型。UVA照射激活RIPK 3并介导小鼠CE和原代人CEC（pHCECs）中的坏死性凋亡。UVA照射与位于RIPK 3下游的关键坏死性凋亡分子（DAI、TRIF和MLKL）的上调相关。此外，原代角膜内皮细胞中的RIPK 3抑制或沉默抑制UVA诱导的细胞死亡，沿着pHCEC中MLKL的下调。此外，在小鼠（RIPK 3 K51 A和RIPK 3 −/−小鼠）中RIPK 3的遗传抑制或敲除类似地减弱了离体UVA照射实验中的细胞死亡和坏死性凋亡水平。总之，这些结果确定RIPK 3，而不是RIPK 1，作为UVA诱导的细胞死亡在CE中的关键调节因子，并表明其作为未来保护靶点的潜力。
Ultraviolet (UV) is one of the most energetic radiations in the solar spectrum that can result in various tissue injury disorders. Previous studies demonstrated that UVA, which represents 95% of incident photovoltaic radiation, induces corneal endothelial cells (CECs) death. Programmed cell death (PCD) has been implicated in numerous ophthalmologic diseases. Here, we investigated receptor-interacting protein 3 kinase (RIPK3), a key signaling molecule of PCD, in UVA-induced injury using a short-term corneal endothelium (CE) culture model. UVA irradiation activated RIPK3 and mediated necroptosis both in mouse CE and primary human CECs (pHCECs). UVA irradiation was associated with upregulation of key necroptotic molecules (DAI, TRIF, and MLKL) that lie downstream of RIPK3. Moreover, RIPK3 inhibition or silencing in primary corneal endothelial cells suppresses UVA-induced cell death, along with downregulation of MLKL in pHCECs. In addition, genetic inhibition or knockout of RIPK3 in mice (RIPK3K51A and RIPK3−/− mice) similarly attenuates cell death and the levels of necroptosis in ex vivo UVA irradiation experiments. In conclusion, these results identify RIPK3, not RIPK1, as a critical regulator of UVA-induced cell death in CE and indicate its potential as a future protective target.
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