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C H A P T E R 18

CELL DEATH

Nika N. Danial and David M. Hockenbery

Cell death is a highly organized fundamental activity that is equally various demands (hypoxia, hypertransfusion), despite widely differ-
complex in regulation as cell division and differentiation. In the ing production rates of mature erythroid cells. The raison d’être
physiologic contexts of embryonic development and tissue renewal, appears to be to overproduce erythroid colony-forming units and
or as a pathologic response to cell injury and infectious pathogens, proerythroblasts at low altitudes, with excess cells removed prior
cell deaths are orchestrated for multiple purposes that benefit the to the erythroblast stage. This scheme provides a rapidly accessible
organism. These include maintenance of epithelial barrier function, reserve under conditions of higher demand.
destruction of microbes, adaptive immune responses, recycling of A final physiologic application for apoptosis is as a mechanism for
biologic macromolecules, intracellular signaling, and preservation selection of specific cell phenotypes. A well-known example occurs
of genomic integrity. The majority of mammalian cell deaths have in the adaptive immune system following clonal diversification of
morphologic and biochemical features of apoptosis (Fig. 18.1), a self- T- and B-lymphocyte antigen receptors by gene recombination
inflicted death program encoded in the genetic material of all cells and error-prone DNA replication. Positive and negative clonal
(Fig. 18.2). Necrosis, an alternative mechanism of cell death, occurs selection to match T-cell receptors to cognate class I and class II
in the aftermath of extreme cellular insults and could be viewed as histocompatibility antigens on accessory cells and elimination of
a failure of cellular homeostasis. Recently, a programmed pathway many receptors reacting with self-antigens takes place in the thymus.
of necrosis, referred to as necroptosis, has been identified. Although Affinity maturation of immunoglobulin-bearing B cells takes place in
cells contain their own death apparatus, cell death in multicellular germinal centers of lymphoid organs. In each case, cells run through
organisms is exquisitely sensitive to the consent of neighboring a gauntlet of near-death experiences, with death and survival signals
cells. As might be expected, the internal cell death machinery is directly linked to the binding properties of the antigen receptor on
tightly interwoven with other essential cell pathways. Investigations individual cells.
of cell death have also informed our understanding of living cells;
for example, the recognition that cellular remodeling shares some
pathways with apoptotic cell death. EXECUTIONERS OF APOPTOSIS
Caspases
PHYSIOLOGIC CELL TURNOVER
The central effectors of apoptosis are a family of cysteine proteases
1
11
An adult human loses approximately 10 cells/day, with skin, known as caspases (cysteinyl aspartate–specific protease). All caspases
intestine, and hematopoietic tissues accounting for the majority. are aspartases with a four residue recognition sequence P4–P1 (Fig.
Apoptotic cell death in the adult occurs most clearly in the context 18.3). A serine protease that also recognizes aspartic acid motifs,
of cyclically renewing (endometrium, breast, hair follicle) tissues. granzyme B, is similarly involved in cytolytic T-cell killing. Often
Homeostatic mechanisms in skin and intestine balance generation only one or two caspase cleavage sites are found in a variety of cellular
of new cells with loss of terminally differentiated cells, principally by proteins, in many cases members of the same complex or biochemical
nonapoptotic mechanisms. In the intestinal epithelium, terminally pathway, leading to limited digestion of substrate proteins. Proteins
differentiated enterocytes migrate onto the epithelium surface and are truncated by caspase cleavage frequently exhibit altered functions,
extruded as viable cells, triggered by cellular crowding. Keratinocytes demonstrating that caspases can act as signaling proteases. The
in the external layer of skin undergo a process of cornification to form number of identified caspase substrates is over 1500. 2
an epithelial barrier before being shed. While no single caspase substrate has been identified that is
Neutrophils recruited to sites of inflammation undergo apoptosis obligate for cell death, some progress has been made in attributing
upon removal of the inflammatory stimulus. Apoptotic neutrophils biochemical and morphologic features of apoptotic death to prote-
are unable to degranulate, and reprogram macrophages to an anti- olysis of specific substrates. Caspase-mediated cleavage and activa-
inflammatory phenotype when phagocytosed (termed efferocytosis). tion of Rho-associated kinase-1 (ROCK1) stimulates actin–myosin
This clearance mechanism is specialized to apoptotic neutrophils, contractility, leading to membrane blebbing and fragmentation of the
as necrotic neutrophils and opsonized cells trigger macrophages to nucleus weakened by cleavage of nuclear lamins. DNA fragmenta-
secrete inflammatory cytokines. Apoptotic cell death of anucleate tion is mediated by an endonuclease, DNA fragmentation factor 40
platelets controls platelet lifespan, and in the absence of the anti- (DFF40), also known as caspase-activated DNAse (CAD), which is
apoptotic protein BCL-X L , platelets survive 24 h compared with 5 activated following caspase-mediated degradation of an inhibitory
days in wild-type mice. binding partner, ICAD/DFF45. Extracellular release of ATP, a “find-
Reversible physiologic cell deaths also provide a reserve produc- me” signal for macrophages, is triggered by caspase-mediated cleavage
tion capacity for functionally mature cells. The glycoprotein hormone of a C-terminal inhibitory domain from Pannexin 1 channels, and
erythropoietin (EPO) is produced by kidney mesangial cells and outer plasma membrane leaflet exposure of phosphatidylserine, an
stimulates excess red blood cell production in proportion to the “eat-me” signal for efferocytosis, follows caspase-mediated inactiva-
demand for blood oxygen-carrying capacity. The EPO receptor is tion of ATP11C flippase activity.
expressed on committed erythrocyte precursors (erythroid colony- In the intracellular battle between survival and proapoptotic
forming units and proerythroblasts). Growth factors, in general, factors, caspases can also swing the advantage toward death by alter-
also generate survival signals. The primary in vivo effect of EPO is ing the balance of forces. The mitochondrial survival proteins BCL-2
to rescue erythroid precursors from physiologic death. The EPO- and BCL-X L are subject to N-terminal cleavage by caspases. Not
responsive erythroid compartment in the bone marrow and spleen only does N-terminal truncation eliminate a survival function, but
is maintained at a constant size and rate of cell proliferation under the cleaved versions also behave as proapoptotic factors. Activation

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