Why Is Apoptosis Necessary?
Here are some points to keep in mind.
Normally, billions of cells die every day by apoptosis. If
they did not, disaster would follow. The embryo could not “chisel” itself into
the proper shape; the developing nervous system would be distorted by swarms of
unwanted neurons; the maturing immune system would rapidly be overcome by
autoimmune lymphocytes; the epidermis and other surface epithelia would become
absurdly thick; and in the adult, the lack of a mechanism to counterbalance
mitosis would lead to organ deformities incompatible with life.
Apoptosis is planned to perform as Nature's surgical knife:
it acts swiftly (at least twice as fast as oncosis) and quietly (it does not
trigger inflammation, as oncosis does).
Why There Is No Inflammation In Apoptosis?
Granulocytes are rarely seen around apoptotic cells. This in
stark contrast with the response to ischemic necrosis: crowds of granulocytes
and other inflammatory cells pour into the area. The “inflammatory silence” of
apoptosis makes sense: if apoptosis is to carry out its discrete function of
eliminating single unwanted cells, without damage to the tissue structure as a
whole, the neutrophils must be kept out of the picture. When activated, these
cells are known to secrete bactericidal molecules in such large amounts that
collateral damage to bystander cells, as in Inflammation, is bound to occur.
Actually, it is not quite correct to say that apoptosis does
not induce inflammation: macrophages do appear on the scene and phagocytize the
apoptotic cells; and macrophages are almost the prototype of inflammatory
cells.
It is a general rule of inflammation that when macrophages
are activated, they secrete chemical messages to recruit other types of
inflammatory cells; we rationalize this as a call for help. But
macrophages phagocytizing apoptotic cells do not call for help. Quite to
the contrary: they secrete anti-inflammatory substances
such as prostaglandin E2. It seems obvious that the overall plan for
the apoptotic cells is to die in incognito.
Microscopic features of apoptosis
As usual, details vary, but the following description is
representative; the whole performance lasts about an hour, sometimes less
- The cell shrinks, becomes denser (dark by electron microscopy), rounds up and detaches itself from its neighbors. The loss of volume is the first change; it may be as high as 60 percent for eosinophils; it may have the purpose of reducing the labor of phagocytosis. Both shrinkage and density may reflect (a) loss of fluid: the smooth endoplasmic reticulum swells into vesicles that fuse with the cell membrane, dumping out fluid, while the Na/KATP pump extracts cations from the cell; and/or (b) protein cross-linking by transglutaminases, which may also explain the increased density.
- The chromatin becomes very dense, and separates into deeply stained, homogeneous, often semilunar or sickleshaped masses plastered against the nuclear membrane. At least half a dozen factors are known to induce this chromatin condensation, including a factor called acinus and the caspases. We may wonder why the cell takes the trouble of shredding its DNA: the purpose may be to prevent it from being misused.
- Budding: Seen in a time-lapse movie the cell performs a striking (death dance): it sends out and pulls back short processes, which contain dense cytoplasm and often a piece of the nucleus.
- Blebbing: Small blebs may develop, but this is not typical of apoptosis, whereas it is constant and extensive in oncosis. Blebs, blister-like structures with a watery content, are biologically different phenomenon from budding. There has been some confusion between budding and blebbing, because scanning electron micrographs show balloon-like “protrusions” that are difficult to interpret. Another confusing factor is that intermediate forms may also occur.
- The “buds” break off, to become apoptotic bodies.
- What is left of the cell body is taken up by neighboring cells or extruded (in epithelia); or it is phagocytized by macrophages.
- The corpses of apoptotic cells, if shed into a space such as a glandular lumen, may undergo what was called “secondary necrosis”. They can also be picked up by macrophages or by neighboring cells. These former neighbors are induced to cannibalize the remains because they express a number of “eat me signals”, perhaps as many as 10; the most important are a vitronectin receptor, annexin 5, and molecules of phosphatidylserine, normally inserted into the inner leaflet of the cell membrane, but flipped out on the apoptotic cells. Remarkably absent around the corpses are the neutrophils.
