Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair.
Ferroptotic stress promotes the accumulation of pro-inflammatory proximal tubular cells in maladaptive renal repair.
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DOI：
10.7554/elife.68603
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发表时间：
2021-07-19
期刊：
影响因子：
7.7
通讯作者：
Souma T
中科院分区：
文献类型：
--
作者：
Ide S;Kobayashi Y;Ide K;Strausser SA;Abe K;Herbek S;O'Brien LL;Crowley SD;Barisoni L;Tata A;Tata PR;Souma T
过度的脂质过氧化诱导铁凋亡应激和铁凋亡，这是一种非凋亡形式的调节性细胞死亡，与小鼠和人类的适应不良肾修复有关。使用单细胞转录组学和小鼠遗传学方法，我们发现近端肾小管（PT）细胞在损伤后形成分子上不同的促炎状态。虽然这些炎性PT细胞在轻度损伤后短暂出现并恢复其原始状态而不诱导纤维化，但在严重损伤后，它们积累并导致持续性炎症。这种短暂的炎症PT状态显着下调谷胱甘肽代谢基因，使细胞容易受到铁氧化应激的影响。在轻度损伤后，这些细胞中高铁蛋白应激的遗传诱导导致炎性PT细胞的积累，增强炎症和纤维化。我们的研究拓宽了铁中毒应激的作用，从触发调节性细胞死亡到包括促进和积累促炎细胞，这些促炎细胞是适应不良修复的基础。
Overwhelming lipid peroxidation induces ferroptotic stress and ferroptosis, a non-apoptotic form of regulated cell death that has been implicated in maladaptive renal repair in mice and humans. Using single-cell transcriptomic and mouse genetic approaches, we show that proximal tubular (PT) cells develop a molecularly distinct, pro-inflammatory state following injury. While these inflammatory PT cells transiently appear after mild injury and return to their original state without inducing fibrosis, after severe injury they accumulate and contribute to persistent inflammation. This transient inflammatory PT state significantly downregulates glutathione metabolism genes, making the cells vulnerable to ferroptotic stress. Genetic induction of high ferroptotic stress in these cells after mild injury leads to the accumulation of the inflammatory PT cells, enhancing inflammation and fibrosis. Our study broadens the roles of ferroptotic stress from being a trigger of regulated cell death to include the promotion and accumulation of proinflammatory cells that underlie maladaptive repair.