We often hear about a cellular self-destruction program called apoptosis – it is triggered when a cell has received too many mutations or when a virus or bacteria has settled in it. A sick cell causes many problems to those around; apoptosis eliminates the cell along with the problems: dying along with mutations, the cell does not have time to become truly malignant; dying along with the infection, it stops the spread of infection from itself to other cells.
Employees of the Institute of Physical and Chemical Biology (NIIFKhB) named after Belozersky write to International Journal of Molecular Sciencesthat the same general safety mechanism works at the population level – its role is played by innate immunity. He is the first to turn on in response to various troubles, from injuries and infections to ischemic lesions and poisoning with toxins. At the same time, it is well known that innate immunity is prone to overdoing it, so that the disease is more severe than it could, with complications and frequent death in the end. (You don’t have to go far for examples – deaths in coronavirus infection with COVID-19 are often associated with the fact that the immune system has overdone it.) It is believed that excessive activity of immune responses is an evolutionary payback (or a side effect) for the high efficiency of the immune system. That is, immunity quickly relieves us of problems, but in return we need to be prepared for a certain likelihood of complications.
However, there is strong evidence that immune hyperactivity is not a side effect, but a special defense mechanism that prevents the spread of epidemics across populations. The immune system learns about malfunctions with the help of special receptors. The innate immune system has a relatively small number of such receptors that recognize common features inherent in large groups of pathogens. For example, these receptors react to some properties that are found in all viruses, whose genome is encoded in RNA, or on the properties of viruses, whose genome is stored in DNA, or to some peculiarities of different types of bacteria with the same cell wall structure. These molecular properties are called damage-associated molecular patterns (DAMPs). It was believed that they are released into the blood only from damaged cells. DAMPs attract immune cells and stimulate inflammatory signals at sites of tissue damage, promoting wound healing and organ repair.
However, data gradually began to accumulate that many DAMPs leave intact cells during inflammation, and they do not just leave – the cells are actively throwing them out. The most striking example here is the nuclear proteins HMGB1 and CIRP. Normally, they are involved in the regulation of replication and transcription, but once outside the cell, they serve as powerful activators of the immune response. To remove these proteins outside, they need to be specially modified so that they can leave the cell nucleus into the cytoplasm, and then they must be enclosed in membrane vesicles-lysosomes, in which HMGB1 and CIRP will go outside.
Proteins HMGB1 and CIRP, and besides them, other DAMPs play a huge role in the development of many pathologies. And if mice, for example, turn off the CIRP gene, they can survive sepsis, which would simply kill them if CIRP was working. By using antibodies that intercept some DAMPs or block their receptors, it is possible to prevent the development of sepsis, aseptic systemic inflammation, ischemic lesions, etc. Let’s not forget that the same CIRP, normal, intact cells are trying to specifically show the immune system, making remarkable efforts for this. All this is difficult to explain from the point of view of the protective function of immunity, but they are in good agreement with the hypothesis of programmed suicide: just as the cellular self-destruction program kills the cell along with the infection, so the innate immunity together with the infection kills the sick individual.
Incidentally, a fundamentally similar strategy called the “abortive infection system” works in bacteria. Usually it is only two proteins that cause bacteria to suicide when infected with a virus (phage). It has been shown experimentally that bacteria with such a system benefit from a viral infection in those who are deprived of it (we are not talking about individual bacteria, but about the community).
The hypothesis of altruistic programmed death (phenoptosis) of individual organisms for the benefit of the population was formulated by Vladimir Skulachev more than two decades ago. In addition to acute phenoptosis, which can be illustrated by what happens to patients with covid, Vladimir Skulachev suggested the existence of slow phenoptosis, which, in fact, is programmed aging. Indeed, there are quite convincing examples of how the activity of innate immunity and aging are related. So, if we select the longest-living among Drosophila flies for many years, we will end up with long-lived flies with a suppressed immune system. Something similar, apparently, happened in nature with bats, in which, due to a mutation in one gene, antiviral immunity was significantly reduced. Bats followed the path of peaceful coexistence with many viruses, however, as a result, they became a reservoir of many very dangerous pathogens. Perhaps it is due to the weakening of immunity that bats live much longer (10–20 years, and some species even up to 40 years) than most animals of a similar size.
According to Boris Chernyak, head of the cell bioenergy laboratory at the N.I. A.N. Belozersky and one of the co-authors of the article, it is sad to realize that we carry in ourselves a program that can kill us and at the same time serves as a driver of aging. But if we know how this program works, then we can try to find means that would suppress it. After all, we also have adaptive immunity, antibiotics and antiviral drugs, so death is hardly necessary. One of the possible drugs against phenoptosis can be mitochondria-targeted antioxidants, such as SkQ1, developed at the Research Institute of Physical Chemistry and Biology under the leadership of V.P. Skulachev. SkQ1 suppresses many reactions of innate immunity and, apparently, this is what determines its therapeutic effect in a variety of pathologies, as well as the fact that the drug significantly increases the average life span of laboratory animals. Unlike many anti-inflammatory drugs, SkQ1 has no significant side effects. Perhaps the development and use of such drugs can make our lives longer and safer.
This work was supported by the Russian Science Foundation.
Based on materials from the press service of Moscow State University.
Source: Автономная некоммерческая организация "Редакция журнала «Наука и жизнь»" by www.nkj.ru.
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