Cells in the body dying of necroptosis obey Dylan Thomas — “Do not go gentle into that good night” all sorts of inflammation ensues around the cell, and systemically if enough die that way at once.
Cells dying from the first discovered form of programmed cell death e.g. apoptosis disobey. They die very quietly producing no inflammation, and are quietly munched up by phagocytes. Just how this happens has been a huge mystery.
Well one way to figure out what is going on looks at a phagocyte before it meets an apoptotic cell and afterwards. Quite a bit it turns out. The brute force technique looks at the changes in our 20,000 or so protein coding genes. They found increased expression in 886 and decreased expression in 966, some 9% of our total. How do you make sense of that.
This is typical of the brute force approach to any condition (e.g. cancer, infection, vascular disease), and shows you just how hard it is to figure out what is going on from the mass of data produced.
The authors of Nature vol. 580 pp. 130 – 135 ’20 (https://www.nature.com/articles/s41586-020-2121-3.pdf) were far cleverer than that. What they did was cause a bunch of cells to go apoptotic at once and then the “supernatants and cell pellets from apoptotic cells and live cell controls were subjected to untargeted metabolomic profiling against a library of more than 3,000 biochemical features or compounds.”
Then by a huge amount of work they found 6 metabolites released by the apoptotic cell which when given together which could switch macrophages (a type of phagocyte)to the non-inflammatory state (e.g. the one above producing all those gene changes).
Then they pared the number of metabolites doing this down to 3 (spermidine, guanosine monophosphate and inosine monophosphate). They call this cocktail of metabolites MEMIX-3.
They get out of the cell dying of apoptosis because the executioner (caspase) chops up a protein channel on the cell surface (pannexin1), allowing the 6 metabolites to escape. A rather parsimonious suicide note wouldn’t you think.
It gets better. MEMIX-3 obviously is an anti-inflammatory agent, and they showed that it attenuates arthritic symptoms and prevents rejection of a lung transplant.
Brilliant work, and possibly one of great therapeutic import.
Chemiotics II 