Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

THE INNATE IMMUNE SYSTEM
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The activation of PRRs results in the production of a large variety of extracellular
signal molecules that mediate the inflammatory response at the site of an
infection. These include both lipid signal molecules, such as prostaglandins, and
protein (or peptide) signal molecules called cytokines. Some of the most important
pro-inflammatory cytokines are tumor necrosis factor-α (TNFα), interferon‐γ
(IFNγ), a variety of chemokines (which recruit leukocytes), and various interleukins
(ILs) that we discuss later, including IL1, IL6, IL12, and IL17. In addition, a
secreted PRR (mannose-binding lectin) activates the complement system when
the PRR binds to a pathogen; fragments of complement proteins released during
complement activation stimulate an inflammatory response (discussed shortly;
see Figure 24–7).
When activated by PAMPs, most cell-surface and intracellular PRRs stimulate
the production of multiple pro-inflammatory cytokines by activating intracellular
signaling pathways that switch on transcription regulators, including NFκB,
to induce the transcription of the relevant cytokine genes (see Figure 15–62).
Some PRRs, however, can also stimulate pro-inflammatory cytokine production
by a different mechanism: when activated, several cytoplasmic NLRs assemble
with adaptor proteins and specific protease precursors of the caspase family (discussed
in Chapter 18) to form inflammasomes, in which pro-inflammatory cytokines
such as IL1 are cleaved from their inactive precursor proteins by activated
caspases. These cytokines are then released from the cell by a poorly understood,
unconventional secretion pathway. Inflammasomes closely resemble apoptosomes
in their assembly and structure, but, in apoptosomes, procaspases are
activated to initiate a proteolytic caspase cascade that leads to apoptosis (see Figure
18–7).
NLR-dependent inflammasome assembly can also be triggered in the absence
of infection if cells are damaged or stressed. Such cells produce “danger signals,”
such as altered or misplaced self molecules, which can activate the relevant NLRs:
the arthritis caused by uric acid crystals formed in the joints of individuals with
gout, who have abnormally high uric acid levels in their blood, is a painful example.
dividing
bacterium
pseudopod
plasma
membrane
Phagocytic Cells Seek, Engulf, and Destroy Pathogens
In all animals, the recognition of a microbial invader is usually quickly followed by
its engulfment by a phagocytic cell. Macrophages are long-lived phagocytes that
reside in most vertebrate tissues; they are among the first cells to encounter invading
microbes, whose PAMPs activate the macrophages to secrete pro-inflammatory
signal molecules. Neutrophils are short-lived phagocytes that are abundant
in blood but are not present in healthy tissues; they are rapidly recruited to sites of
infection by various attractive molecules, including formylmethionine-containing
peptides (which are released by microbes but are not made by mammalian
cells), chemokines secreted by activated macrophages, and peptide fragments
produced from cleaved, activated complement proteins. The recruited neutrophils
contribute their own pro-inflammatory cytokines.
In addition to their PRRs, macrophages and neutrophils display a variety of
cell-surface receptors that recognize fragments of complement proteins or antibodies
bound to the surface of a pathogen. The binding of such a pathogen to these
receptors leads to its phagocytosis (Figure 24–5) and an attack on the ingested
pathogen once inside a phagolysosome. The phagocytes possess an impressive
armory of weapons to kill the invader, including enzymes such as lysozyme
and acid hydrolases that can degrade the pathogen’s cell wall. The cells assemble
NADPH oxidase complexes on the phagolysosomal membrane, where the
complexes catalyze the production of highly toxic oxygen-derived compounds,
including superoxide (O – 2 ), hydrogen peroxide, and hydroxyl radicals. A transient
increase in oxygen consumption by the phagocytic cells, called the respiratory
burst, accompanies the production of these toxic compounds. Whereas macrophages
generally survive this killing frenzy and live to kill again, neutrophils do
not. Dead and dying neutrophils are a major component of the pus that forms
in acute bacterially infected wounds; their half-life in the human bloodstream is
only a few hours.
phagocytic
leukocyte
(neutrophil)
secretory
vesicles
1 µm
Figure 24–5 Antibody-activated
phagocytosis. Electron micrograph of
a neutrophil phagocytosing an antibodycoated
bacterium, which is in the process
of dividing. The process in which antibody
(or complement) coating of a pathogen
increases the efficiency with which the
pathogen is phagocytosed is called
opsonization. (Courtesy of Dorothy F.
Bainton, MBoC6 from R.C. m25.24b/24.06
Williams, Jr. and
H.H. Fudenberg, Phagocytic Mechanisms
in Health and Disease. New York:
Intercontinental Medical Book
Corporation, 1971.)