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1001 ways to die… or not!

Alea jacta est? Is death already programmed or is it accidental? Is there a purpose in dying? Can death be avoided? For centuries these questions have paved human life, and a few decades ago these burning philosophical issues have been redirected by scientists to the very brick of our tissues -the cell- examining the possible existence of mechanisms that regulate cell death. We now estimate that more than 60 billion cells in our body die every day. The reason is simple: cell death, as well as cell proliferation and differentiation, represents physiological and fundamental processes in the life of every multicellular organism.


The facets of death

When I began to work on AIDS, our team showed that the loss of CD4+ T cells (key cells of the immune system) induced during HIV infection resulted from the suicide of these cells. This discovery played an important role in the growing interest of the whole scientific community in cell death. Three decades later, a plethora of ways to die have been discovered: necrosis, apoptosis, autophagic cell death, NETosis, pyroptosis, parthanatos, necroptosis, ferroptosis and many others (1). We can now state that cell death can either be accidental or precisely programmed. « Accidental cell death » (ACD) occurs when cells are exposed to toxins, or dramatic injuries. These conditions induce a rapid loss of ion-flux control from the cell which passively swells until its membrane ruptures (necrosis). This breakage spills out intracellular contents that in turn recruit immune cells causing an inflammatory response and damaging collateral tissues. For example, ACD is responsible for the first wave of neuron death in the brain following an ischemic stroke. This unpredictable and passive demise strongly contrasts with « Regulated Cell Death » (RCD) a group of processes that are physiological and that actively engage the cells in their own demise. RCD displays different faces such as cell suicides, auto-cannibalism and serial killing. They are induced by different situations, have their own features (machinery, roles, impact on other tissues/immune cells) and are beneficial for the organism (2). Let’s have a look at some of the more characterised RCD pathways.


« Apoptosis » is a form of regulated cell suicide that is triggered to eliminate cells and to preserve the integrity of surrounding tissues. During apoptosis cells shrink, retain their cytoplasmic content to avoid inflammatory reactions and express « eat me » signals to get safely eliminated by professional scavengers. This RCD process occurs during the development of every multicellular organism as illustrated by the remodelling of tadpole tissues during amphibian metamorphosis (3).


During microbial infections, immune cells can also engage into RCD processes to fight against the invaders: Neutrophils sacrifice themselves by « NETosis ». In this process, these cells eject DNA from their own nucleus to form web-like structures that trap and kill extracellular pathogens. Macrophages can lyse themselves by « necroptosis » or « pyroptosis » to release highly potent molecules involved in cellular communication that attract immune cells to the site of infection. During pyroptosis, intracellular microbes are also exposed out of the dying cell to elicit their elimination by immune cells.


Under unfavourable situations such as starvation, stress or hypoxia, cells can engage in « autophagy », a survival process of auto-cannibalism that digests and recycles nutrients from the cell’s own components. However, this initially protective pathway can become excessive under severe conditions and generate irreversible damages that trigger the cell’s demise, called « autophagic cell death ».


Dangerous cells such as infected or cancerous cells can be eliminated by highly efficient killer cells, such as Natural Killer cells and cytotoxic T lymphocytes (CTL). These serial killers deliver to them « the kiss of death », a deadly interaction that perforates their membrane and triggers their apoptosis program (4).


Die another day

The RCD pathways constitute key physiological processes, but can also be dysregulated and involved in the development of human diseases. As a matter of fact, RCD can be abnormally delayed, or even completely blocked, during some infections and cancer. Moreover, viruses, intracellular bacteria and parasites have adopted strategies to evade RCD programs of their host cells to safely settle, replicate and avoid elimination. By inhibiting RCD executioners or activating prosurvival factors, they can efficiently block the cascade of events leading to cell demise (5). Apoptosis can be partially inhibited during infection (like in macrophages hosting the parasite Leishmania), or indefinitely prevented in cancer cells. This is illustrated by HeLa cells that were derived from the biopsy of the cervical cancer of an afro-american woman in 1951, and that are still alive in laboratories all over the world. It has been estimated that several tons of these cells have been grown so far, enabling numerous scientific advances on human pathologies -including AIDS, cancer- and on human papillomavirus and polio vaccines (6).


In contrast, cell death is exacerbated during heart diseases and chronic diseases such as AIDS, auto-immune disorders, rheumatic or neurological diseases. In some cases, several RCD pathways can even act in concert to participate in the pathological process as illustrated by the contribution of apoptosis, necroptosis, pyroptosis and NETosis to rheumatic disease (7).


Memento mori

Understanding the precise regulation of RCD pathways has led scientists to propose cell-death based therapies to restore normal RCD levels during human diseases. Triggering apoptosis is a major strategy in cancerology: several drugs that activate key steps of the apoptosis process or that inhibit anti-apoptotic signals in the cell have been designed and applied to treat different types of cancer (8). Conversely, pharmacological inhibition of RCD can also be intended to reduce damages induced during ischaemia and traumatic injuries.


As thinking about our own death can allow us to remember what's really important to us and live intentionally, developing death-based approaches for tomorrow’s treatments (9) will constitute encouraging strategies to live better.


References

1. Galluzzi, L. et al. (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell death and differentiation doi:10.1038/s41418-017-0012-4.


2. Davidovich, P. et al. (2014) Inflammatory outcomes of apoptosis, necrosis and necroptosis. Biological chemistry doi:10.1515/hsz-2014-0164.


3. Ishizuya-Oka, A. et al. (2010) Apoptosis in amphibian organs during metamorphosis. Apoptosis : an international journal on programmed cell death doi:10.1007/s10495-009-0422-y.

4. Trambas, C. M. et al. (2003) Delivering the kiss of death. Nature immunology doi:10.1038/ni0503-399.


5. Tummers, B. et al. (2022) The evolution of regulated cell death pathways in animals and their evasion by pathogens. Physiological reviews doi:10.1152/physrev.00002.2021.


6. Werb, Z. (2010) Living forever. Nat Med doi:10.1038/nm1010-1071.


7. Anderton, H. et al. (2020) Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease. Nature reviews. Rheumatology doi:10.1038/s41584-020-0455-8.


8. Carneiro, B. A. et al. (2020) Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol doi:10.1038/s41571-020-0341-y.


9. Singh, R. et al. (2019) Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nature reviews. Molecular cell biology doi:10.1038/s41580-018-0089-8.


This article was specialist edited by Dr. Romain Levayer and copy edited by Camila Valenzuela.

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