• Clearance of apoptotic cells. Apoptotic cells and their fragments entice phagocytes by producing a number of “eat-me” signals. For instance, in normal cells, phosphatidylserine is present on the inner leaflet of the plasma membrane, but in apoptotic cells this phospholipid “flips” to the outer leaflet, where it is recognized by tissue macrophages, leading to phagocytosis of the apoptotic cells. Cells that are dying by apoptosis also secrete soluble factors that recruit phagocytes. The plasma membrane alterations and secreted proteins facilitate prompt clearance of the dead cells before the cells undergo membrane damage and release their contents (which can induce inflammation). Numerous macrophage receptors have been shown to be involved in the binding and engulfment of apoptotic cells. The phagocytosis of apoptotic cells is so efficient that dead cells disappear without leaving a trace, and inflammation is virtually absent.
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MORPHOLOGYInH&E-stainedtissuesections,thenucleiofapoptoticcellsshowvariousstagesofchromatincondensationandaggregationand,ultimately,karyorrhexis(
Fig.2.13 );atthemolecularlevel,thisisreflectedinthefragmentationofDNAintonucleosome-sizedpieces.Thecellsrapidlyshrink,formcytoplasmicbuds,andfragmentintoapoptoticbodiesthatarecomposedofmembrane- boundpiecesofcytosolandorganelles(Fig.2.11 ).Becausethesefragmentsarequicklyextrudedandphagocytosedwithoutelicitinganinflammatoryresponse,evensubstantialapoptosismaybehistologicallyundetectable.
In addition to necrosis and apoptosis, two other patterns of cell death have been described that have unusual features. Although the importance of these pathways in disease remains to be established, they are the subjects of considerable current research, and it is useful to be aware of the basic concepts.
Necroptosis. This form of cell death is initiated by engagement of TNF receptors as well as other, poorly defined triggers. Unlike the extrinsic pathway of apoptosis, which also is downstream of TNF receptors, in necroptosis, kinases called receptor-interacting protein (RIP) kinases are activated, initiating a series of events that result in the dissolution of the cell, much like necrosis. The name necroptosis implies that there are features of both necrosis and apoptosis. Some infections are believed to kill cells by this pathway, and it has been hypothesized to play a role in ischemic injury and other pathologic situations, especially those associated with inflammatory reactions in which the cytokine TNF is produced. However, when and why it occurs and how significant it is in human diseases is not well understood.
Pyroptosis. This form of cell death is associated with activation of a cytosolic danger-sensing protein complex called the inflammasome (Chapter 5). The net result of inflammasome activation is the activation of caspases, some of which induce the production of cytokines that induce inflammation, often manifested by fever, and others trigger apoptosis. Thus, apoptosis and inflammation coexist. The name pyroptosis stems from the association of apoptosis with fever (Greek, pyro = fire). It is thought to be one mechanism by which some infectious