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ADAM 17‐triggered TNF signalling protects the ageing Drosophila retina from lipid droplet‐mediated degeneration
Author(s) -
Muliyil Sonia,
Levet Clémence,
Düsterhöft Stefan,
Dulloo Iqbal,
Cowley Sally A,
Freeman Matthew
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2020104415
Subject(s) - biology , microbiology and biotechnology , neurodegeneration , microglia , retinal degeneration , retina , inflammation , tumor necrosis factor alpha , signal transduction , reactive oxygen species , neuroglia , immunology , neuroscience , central nervous system , pathology , medicine , disease
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 ADAM 17/ TACE , and a lipid droplet ( LD )‐mediated mechanism of protecting retinal cells from age‐related degeneration. Loss of ADAM 17, 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 LD s. We show that the glial LD s initially buffer the cells against damage caused by glial and neuronally generated reactive oxygen species ( ROS ), but that in later life the LD s 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.