Unchecked, however, apoptosis can cause great harm as in some neurodegenerative diseases, like multiple sclerosis. Currently, apoptosis is probably the most well-understood version of cell death, but there's still room to learn more, as Stanford scientists demonstrated with the recent discovery that apoptosis spreads through a single cell a lot like falling dominoes.
For many years, scientists had really only identified apoptosis, leaving everything else as necrosis, which at the time basically amounted to, "We don't have a molecular explanation for this type of cell death. It's no joke, NETosis involves death by little structures that look like nets. Specifically, these "nets" come from a type of immune cell called a neutrophil — NET stands for neutrophil extracellular trap. Neutrophils are one of the first immune cells to respond to a microbial invader or infection.
Microbial infections can spark NETosis, leading to an unleashing of anti-microbial net trap that target invading microbes such as bacteria, viruses, parasites or fungi. On the flip side, NETosis can also occur in autoimmune diseases like lupus and rheumatoid arthritis, when the net-like defense structures overstimulate an immune response.
Pyroptosis is also an infection-related form of cell death, but it's "pro-inflammatory" meaning that it comes with something of an alert system that lets neighboring cells know there's infectious trouble on the loose. Thus, it occurs only in a pathological situation. Actually, other than Cyt-c, there are many proteins that are compartmentalized in a sort of organelle of the cell because they function differently in physiological and pathological situations; lysosomal enzymes are another example, as the enzymes will digest out the cell and kill it once they have leaked out from the lysosome to the cytoplasm.
Therefore, the well-characterized caspase-Cyt-c pathway of cell death is actually a mechanism of SICD, but not of apoptosis, in our opinion [ 69 ]. In other words, it is currently unclear whether SICD borrows the death program from apoptosis or uses one different from that of apoptosis. We are all familiar with a phenomenon that a stressful life ages people more quickly. Therefore, stress, even when it is too mild to directly kill cells via necrosis or SICD, may be an impetus for cellular aging leading to SD, probably in part by affecting telomere length [ 70 ].
Relationships between different extents of stress and different cell death modes. Very mild stress may impel cellular aging, leading to an earlier SD of the affected cells. Stress may also hasten apoptosis, although this conjecture still lacks concrete supporting evidence since few in vivo studies focus on unadulterated apoptosis.
A stronger stress may cause SIaLCD and an even stronger stress may cause SInLCD with more dead cells exceeding the clearance capacity of scavenger cells and decaying to cellular shards to agitate inflammation. A severe stress will directly kill cells via necrosis. Apoptosis as a suicide, and necrosis as a homicide, are irreconcilable to each other.
SICD as another death mode resides between apoptosis and necrosis with many similarities and disparities to the two, as summarized in Fig. First, SICD occurs to the useful cells and is a pathological event, which resembles necrosis but starkly contrasts with apoptosis.
Second, because in SICD it is the useful cells that die, cell regeneration, wound healing and probably also scar formation ensue, which again resembles necrosis but contrasts with apoptosis that eliminates archaic cells and therefore does not trigger regeneration. Because of the need for regeneration and wound healing, SICD involves complex communications between the dooming cells and the surrounding healthy cells on such important issues as how many cells need to be regenerated, when and where the minted cells should emerge, as well as whether fibroblasts need to step into help heal the wound.
Although necrosis is also followed by regeneration, its homicidal nature and the resulting swiftness of cell death may not allow for such complicated cell—cell communication. Since SICD is a programmed suicidal procedure, it resembles apoptosis by enticing scavenger cells to dispose of the cell corpse via complicated communications between the predator and the prey to coordinate the time and the location of the predation.
Both apoptosis and SICD may involve communications between the dying cells and their healthy siblings, but this aspect has gained little attention and few explorations. Third, if in SICD the death tally is exceedingly high and goes beyond the clearance capacity of scavengers, i. Fourth, apoptosis can only occur in vivo but SICD and necrosis can occur in cell culture as well. Reiterated more clearly, SICD is well studied with much of the mechanism s well illustrated from cell lines in culture while unadulterated apoptosis is poorly studied with the mechanism s largely unknown.
Useful cells, either healthy or damaged ones, can age and eventually die of SD, but whether obsolete cells also undergo SD is an intriguing question that remains murky, because these cells may be removed much more efficiently via apoptosis. Moreover, SInLCD resembles necrosis that will cause regeneration and wound healing, probably in association with scar formation, but these activities do not follow SIalCD and apoptosis. For those cell types that retain a regeneration ability, regeneration follows SD as it is the useful cells that die, making SD similar to SICD and necrosis but dissimilar to apoptosis.
Since, as aforementioned, apoptosis, as well as regeneration following SD, SICD and necrosis, require different spectra of cell—cell communication and interaction, SD has similarities and differences with apoptosis, SICD and necrosis in this aspect. In our opinion, of the many cell death modes described in the literature, some are ad-hoc variants of apoptosis or SD in different physiological situations, while most others are ad-hoc variants of SICD in different pathological situations or in different cell lines because SICD resides between apoptosis and necrosis.
For example, pyroptosis is SICD of macrophages in which pyrogens can be released to cause hyperthermia [ 28 ]. Although few studies have been conducted to explore the mechanisms of authentic apoptosis in vivo, there is some in vivo evidence supporting this conjecture: post-weaning involution of mouse mammary glands does not show aberrant activation of caspases and their downstream effector protein PARP-1 [ 71 ], and still occurs normally in caspase-3 knockout mice [ 72 ].
Moreover, apoptotic death of mammary tumor cells in c-myc transgenic mice is actually associated with a decreased expression of Cyt-c [ 73 ]. However, a caveat needs to be given that these many ad-hoc variants of the four basic cell death modes are still meaningful and worth exploring as they reflect cell death, mainly SICD, at different particular circumstances, understanding of which is an important scientific footing for precision medicine or personalized medicine.
Stress can directly kill cells necrosis , can turn on intrinsic death program of cells SICD , and can goad aging-caused cell death SD , depending on the extent of stress and the cell type, as different cell types can withstand different extents of stress. For instance, as an adverse event, a given radiotherapy or chemotherapy can directly kill some normal cells necrosis but can only cause SICD or spur SD of some other normal cells while having no effect at all on a third set of normal cells, creating heterogeneity of cell death in a given tissue or organ.
Actually, heterogeneity of cell death is a common phenomenon when a tissue encounters a strong stressor [ 74 ]. It is also possible that a given stress causes death of the same cell via combined mechanisms, including SD, SICD and necrosis. In our cogitation, it is not that necrosis can also be a programmed event but it is because SICD is misconstrued as necrosis. Also, it is not that apoptosis may be immunogenic as well, as alleged in many studies [ 2 ], but it is because SICD is misconstrued as apoptosis.
All animals, including humans, have been programmed in their nuclear and probably also mitochondrial genomes to die eventually, and all cells in an animal will die along with the animal itself, if not earlier. There hitherto has not been any way to immortalize an animal, and not even an organ, but individual cells can be easily reprogrammed to be immortal, either spontaneously as bespoken by benign or malignant tumor cells appearing in humans, or intentionally as cancer researchers often do in labs.
Therefore, the program of cellular SD is not the program of aging of the organ or the animal. A related question that is still under debate is whether prokaryotic and unicellular eukaryotic cells undergo aging, since these unicellular organisms, typically bacteria, maintain their species by constant cell division [ 58 , 75 ]. Cancer cells are immortal and, even after the patient has died, can survive perpetually as cell lines, in which situation individual cancer cells resemble such unicellular organisms as bacteria that keep dividing to maintain themselves.
What still awaits clarification is whether cancer cells and even benign tumor cells also age, and thus also undergo SD, since in so many studies senescence is another nomenclature of cellular aging and since there are plentiful publications describing senescence of cancer cells [ 76 ].
In our logic, stress of any kind, such as an irradiation or a chemotherapy, is unable to induce or accelerate SD of immortal cells, such as cancer cells and various cell lines, either in vivo or in vitro, although it can kill these cells via necrosis or SICD. We are also contemplating over whether apoptosis, SD and SICD are really programmed events as stated in this and almost all other relevant articles. A program is a pre-determined procedure, which in our opinion opposes the fact that most cells in animals are very plastic and can easily adapt to different changes in their microenvironment with a purpose for survival or for a better life, just like those of us who crave for a better life and increased longevity.
The fact that there have been so many ad-hoc modes of programmed cell death identified demonstrates the extreme flexibility of demise programs. If a program can be changed easily, i.
Another question over which we have for long been pondering is whether apoptosis as a pure physiological event developed evolutionarily is encoded by a cellular structure, irreversible change of which is responsible for the irreversibility of the cell death procedure.
Or is apoptosis just like aging and type 2 diabetes that, unlike most other biological functions, lack a structural basis as some of us have wrangled before [ 58 ]? This is because no such cellular structure has been identified yet that is uniquely responsible for authentic apoptosis. What bedevils us the most is such a notion that necrotic cells putrefy to release immunogenic cellular materials to instigate inflammation.
Although this is true in lytic necrosis and probably at a late stage of some other types of necrosis, Fig. This trait seems dissonant with the above description that inflammation is one of the consequences and hallmarks of necrosis, but few articles discuss this incongruity. We opine that there only two basic physiological cell death mechanisms, i.
SICD and necrosis. SICD dwells between apoptosis and necrosis with similarities and differences between the two, which often makes it misconstrued as apoptosis or necrosis. More complicatedly, SICD can be easily adapted to different particular situations to become different variants that are named differently in the literature.
Authentic apoptosis does not occur in cell lines whose original death program has been reprogrammed to make the cells immortal, and does not occur in cell culture that is a stress to cells, uses cell lines, and lacks other cell types as other important players of apoptosis. Many similarities and disparities among apoptosis, SD, necrosis and SICD delineated in this essay should help peers to distinguish these four basic cell death modes, and the variants derived from them, from one another.
Particularly, apoptosis has evolutionarily developed to purge no-longer useful cells from the host tissue or organ, which is a yardstick to differentiate itself from SD, SICD and necrosis that cause death of useful cells and thus are followed by regeneration, wound healing and probably also scar formation. Some notions, which have been ingrained in cell death research and firmly entrenched in the mind of many peers but may be preposterous, are also described in this essay as unanswered conundrums for future exploration and for peers to debate.
How many ways to die? How many different models of cell death? Cell Death Differ. Essential versus accessory aspects of cell death: recommendations of the NCCD Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death Necroptosis: who knew there were so many interesting ways to die? An overview of pathways of regulated necrosis in acute kidney injury.
Semin Nephrol. Regulated necrosis and its implications in toxicology. The morphology of various types of cell death in prenatal tissues. Clarke PG, Clarke S. Nineteenth century research on cell death. Exp Oncol.
Krishna S, Overholtzer M. Mechanisms and consequences of entosis. Cell Mol Life Sci. Programmed necrosis in inflammation: toward identification of the effector molecules. Article PubMed Google Scholar.
Aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J Cell Physiol. Matters of life and death.
Hanson B. Necroptosis: a new way of dying? Cancer Biol Ther. The importance of being dead: cell death mechanisms assessment in anti-sarcoma therapy. Professor Suzanne Cory. Read more about Professor Suzanne Cory. Dr Anna Coussens. Read more about Dr Anna Coussens. Associate Professor Grant Dewson. Associate Professor. Read more about Associate Professor Grant Dewson. Associate Professor Daniel Gray. Joint Division Head.
Read more about Associate Professor Daniel Gray. Associate Professor Marco Herold. Read more about Associate Professor Marco Herold. Professor David Huang.
Read more about Professor David Huang. Associate Professor Gemma Kelly. Read more about Associate Professor Gemma Kelly. Associate Professor Ruth Kluck. Read more about Associate Professor Ruth Kluck. Professor David Komander. Division Head. Read more about Professor David Komander. Professor Guillaume Lessene. Read more about Professor Guillaume Lessene. Associate Professor James Murphy. Read more about Associate Professor James Murphy. Professor John Silke. Read more about Professor John Silke.
Dr Brad Sleebs. Read more about Dr Brad Sleebs. Professor Andreas Strasser. But unfortunately, programmed cell death is not a foolproof mechanism. When things go wrong, it can have dire consequences. Cancer , autoimmune conditions, and neurodegeneration are all linked to failures of normal cell death and cell clearance. There are several different ways that a cell can die. Whatever is at the root of cell death, the corpse lodged in the tissue cannot stick around forever.
Here, we enter the realm of the phagocytes, which are specialized white blood, or epithelial, cells that are able to swallow, or engulf, dying cells. They are also the gatekeepers of inflammation , and cell death can either be pro- or anti-inflammatory, leading to different outcomes. During apoptosis, a cell is broken up and packaged into small, self-contained pieces, which are easily recycled by phagocytes.
Apoptosis is often kick-started by an accumulation of stress signals, such as damaged DNA or low oxygen. This causes leaks in the membranes of mitochondria, which are the powerhouses that convert oxygen into energy in the cell. Once mitochondria are damaged, a cell is well and truly on its way to becoming a corpse. Apoptosis can also be initiated by outside triggers.
These activate so-called death receptors on the cell. The main hallmark of necrotic cell death is swelling leading to rupture of the cell membrane. This leads to components leaking out from inside the cell, in much the same way that air leaks from a tyre with a puncture.
Necrosis happens in response to high temperature or high pressure. Scientists call this the passive form of necrosis, as it does not require any specific activity by the cell. However, there are two forms of necrosis — necroptosis and pyroptosis — which are actively regulated by the cell and are now recognized as specialized forms of programmed cell death. As with passive necrosis, swelling causes the cell to burst. But inside, closely orchestrated sequences of events take place.
There is some evidence that necroptosis may be a backup system that kicks in when certain pathogens, which can inhibit apoptosis, infect a cell.
0コメント