The right death
How dying cells calm the immune system
Kirill Stasevich, Science and Life (nkj.ru ) based on the materials of Nature: Ghostly metabolic messages from dying cells.
Our cells die constantly, and this is quite natural: they age, they wear out, in the end, they often become simply unnecessary: for example, during embryonic development, many cells, having done their job, must give way to others. In this case, the cells do not die suddenly, but according to a certain program called apoptosis, which they themselves include.
With apoptosis, the synthesis of almost all proteins stops, except for a special group of enzymes called caspases. They break down cellular proteins, at the same time organelles in the cell spread into parts, including the nucleus with fragmented DNA, and everything ends with the cell breaking up into small pieces surrounded by membranes. These pieces are absorbed and digested by immune cells-macrophages.
The peculiarity of such cell suicide is that the dying cell does not irritate the immune system. If everything had happened differently, and the cell would have simply ruptured, for example, from mechanical stress, then the immune system would have triggered severe inflammation. In case of unplanned death, a lot of molecules come out of the cell, which normally should only be inside it and nowhere else – for example, the same DNA. If the immune system senses cellular DNA and a number of cellular molecules outside the cell, it understands that something is very much wrong. (However, it is worth clarifying that among the cellular suicide programs there is one called necroptosis, which destroys the cell in such a way as to stimulate the immune system.)
With apoptosis, everything is completely different – dying cells suppress inflammation and stimulate wound healing processes. Obviously, apoptotic cells somehow signal to macrophages eating them that everything is fine and there is no need to call additional immune armed forces. It was these anti-inflammatory signals from dying cells that researchers from the University of Virginia tried to decipher. In an article in Nature (Medina et al., Metabolites released from apoptotic cells act as tissue messengers), they write that cells in apoptosis actually secrete certain substances, and these substances turn out to be the same regardless of the type of dying cell.
Molecular signals from apoptotic cells affect the activity of genes in macrophages. The authors of the work write about six signaling molecules that, in order to properly act on immune cells, must act all together, that is, all six at once. And if we take, for example, three signal molecules, then the activity of genes in macrophages will change, but not very much.
The researchers in their article talk in detail about only three signaling molecules – spermidine, guanosine monophosphate (GMF) and inosine monophosphate (IMF). Spermidine belongs to the class of polyamines and is formed in biochemical reactions associated with the transformations of amino acids. Cells dying by apoptosis enhance the synthesis of spermidine, which exits through a special channel in the membrane formed by the protein pannexin 1. The channel is opened by enzymes caspases – the very ones that organize apoptosis in the cell. That is, the dying cell simultaneously synthesizes the desired signal and creates a channel out for it. (Pannexin 1 removes not only spermidine from the cell, but also other apoptotic signaling molecules.) At the same time, the cells do not release urea from themselves, which is formed in the same reactions as spermidine – urea just stimulates inflammation, so during apoptosis it should not be outside in any way.
Healthy cell (a) and apoptotic (b) – VM.
Spermidine, GMF and IMF are associated with a variety of molecular processes. GMF and IMF act on receptors that send signals to a number of genes, including those associated with immunity. It is also known that inosine, which can be obtained from IMF, very effectively suppresses inflammation. By injecting spermidine, GMF and IMF to mice with arthritis, the researchers were able to ease the symptoms of the disease, which again arise due to severe inflammation; and similarly, using the same three molecules, they were able to weaken immune rejection in mice with a transplanted lung.
How all this works in humans remains to be seen; after all, human receptors are partly different from mouse ones, and, for example, they react to inosine many times weaker. But perhaps the way in which dying cells calm the immune system can be used in the future in medicine – in cases where it is necessary to prevent too strong an immune reaction.
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