Animals have evolved multiple mechanisms to protect themselves from the cumulative effects of age‐related cellular damage. Here, we reveal an unexpected link between the TNF (tumour necrosis factor) inflammatory pathway, triggered by the metalloprotease ADAM17/TACE, and a lipid droplet (LD)‐mediated mechanism of protecting retinal cells from age‐related degeneration. Loss of ADAM17, TNF and the TNF receptor Grindelwald in pigmented glial cells of the Drosophila retina leads to age‐related degeneration of both glia and neurons, preceded by an abnormal accumulation of glial LDs. We show that the glial LDs initially buffer the cells against damage caused by glial and neuronally generated reactive oxygen species (ROS), but that in later life the LDs dissipate, leading to the release of toxic peroxidated lipids. Finally, we demonstrate the existence of a conserved pathway in human iPS‐derived microglia‐like cells, which are central players in neurodegeneration. Overall, we have discovered a pathway mediated by TNF signalling acting not as a trigger of inflammation, but as a cytoprotective factor in the retina.

中文翻译：

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ADAM17 触发的 TNF 信号传导可保护老化的果蝇视网膜免受脂滴介导的退化。

动物已经进化出多种机制来保护自己免受与年龄相关的细胞损伤的累积影响。在这里，我们揭示了由金属蛋白酶 ADAM17/TACE 触发的 TNF（肿瘤坏死因子）炎症通路与脂滴（LD）介导的保护视网膜细胞免受年龄相关性退化的机制之间的意外联系。果蝇色素神经胶质细胞中 ADAM17、TNF 和 TNF 受体 Grindelwald 的缺失视网膜导致胶质细胞和神经元的年龄相关性退化，然后是胶质细胞 LD 的异常积累。我们表明，神经胶质 LD 最初缓冲细胞免受由神经胶质和神经元产生的活性氧 (ROS) 引起的损伤，但在以后的生活中，LD 消散，导致有毒过氧化脂质的释放。最后，我们证明了人类 iPS 衍生的小胶质细胞样细胞中存在一条保守的通路，这些细胞是神经退行性变的核心参与者。总的来说，我们发现了一种由 TNF 信号介导的通路，它不是炎症的触发因素，而是视网膜中的一种细胞保护因子。