Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation.
Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation.
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小胶质细胞坏死性凋亡通过 TLR4 激活导致神经炎症和视网膜变性
DOI：
10.1038/cdd.2017.141
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发表时间：
2018-01
影响因子：
12.4
通讯作者：
He C
中科院分区：
文献类型：
--
作者：
Huang Z;Zhou T;Sun X;Zheng Y;Cheng B;Li M;Liu X;He C
炎症已经成为神经损伤和神经退行性疾病的关键机制。小胶质细胞是视网膜固有免疫细胞，是视网膜神经细胞免疫损伤的主要成分。小胶质细胞参与视网膜炎症是复杂的，在这里我们首次提出小胶质细胞的坏死性凋亡会引发神经炎症并加剧视网膜神经损伤和变性。我们发现，小胶质细胞经历受体相互作用蛋白激酶1（RIP 1）-和RIP 3-依赖性坏死性凋亡不仅在视网膜变性的rd 1小鼠，而且在急性视网膜神经损伤小鼠。坏死性凋亡的小胶质细胞释放多种促炎细胞因子和趋化因子，如肿瘤坏死因子-α和趋化因子（CC基序）配体2，其协调视网膜炎症。重要的是，使用necrostatin-1阻断坏死性凋亡可以抑制小胶质细胞介导的炎症，挽救视网膜变性或预防体内神经损伤。同时，培养的小胶质细胞经历RIP 1/3介导的坏死性凋亡，坏死性凋亡的小胶质细胞产生大量的促炎细胞因子，以响应脂多糖或氧化应激在体外。从机制上讲，TLR 4缺乏可通过降低机械分子RIP 1和RIP 3的表达水平来改善小胶质细胞坏死性凋亡，并抑制视网膜炎症，这表明TLR 4信号传导在小胶质细胞坏死性凋亡介导的炎症中是必需的。因此，我们认为小胶质细胞通过TLR 4激活经历了坏死性凋亡，促进了炎症反应，从而加剧了相当大的神经损伤和变性。因此，坏死性凋亡阻断成为一种新的治疗策略，用于缓和小胶质细胞介导的神经炎症和改善神经损伤和神经退行性疾病。
Inflammation has emerged to be a critical mechanism responsible for neural damage and neurodegenerative diseases. Microglia, the resident innate immune cells in retina, are implicated as principal components of the immunological insult to retinal neural cells. The involvement of microglia in retinal inflammation is complex and here we propose for the first time that necroptosis in microglia triggers neuroinflammation and exacerbates retinal neural damage and degeneration. We found microglia experienced receptor-interacting protein kinase 1 (RIP1)-and RIP3-dependent necroptosis not only in the retinal degenerative rd1 mice, but also in the acute retinal neural injury mice. The necroptotic microglia released various pro-inflammatory cytokines and chemokines, such as tumor necrosis factor-α and chemokine (CC motif) ligand 2, which orchestrated the retinal inflammation. Importantly, necroptosis blockade using necrostatin-1 could suppress microglia-mediated inflammation, rescue retinal degeneration or prevent neural injury in vivo. Meanwhile, cultured microglia underwent RIP1/3-mediated necroptosis and the necroptotic microglia produced large amounts of pro-inflammatory cytokines in response to lipopolysaccharide or oxidative stress in vitro. Mechanically, TLR4 deficiency ameliorated microglia necroptosis with decreased expression levels of machinery molecules RIP1 and RIP3, and suppressed retinal inflammation, suggesting that TLR4 signaling was required in microglia necroptosis-mediated inflammation. Thus, we proposed that microglia experienced necroptosis through TLR4 activation, promoting an inflammatory response that serves to exacerbate considerable neural damage and degeneration. Necroptosis blockade therefore emerged as a novel therapeutic strategy for tempering microglia-mediated neuroinflammation and ameliorating neural injury and neurodegenerative diseases.