Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
EMBO J. 2020 Sep 1;39(17):e104415. doi: 10.15252/embj.2020104415. Epub 2020 Jul 26.
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.
动物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 TNF（肿瘤坏死因子）炎症途径与脂滴（LD）介导的保护视网膜细胞免受与年龄相关的变性的机制之间的意外联系。果蝇视网膜色素胶质细胞中金属蛋白酶 ADAM17/TACE 触发的 TNF 炎症途径和 TNF 受体 Grindelwald 的缺失导致胶质和神经元的年龄相关性退化，之前是胶质 LD 的异常积累。我们表明，最初，胶质 LD 缓冲细胞免受由胶质和神经元产生的活性氧（ROS）引起的损伤，但在生命后期，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 衍生的小胶质样细胞中存在保守途径，小胶质样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 信号介导的途径，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。
