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1058 Part VIII: Monocytes and Macrophages Chapter 67: Structure, Receptors, and Functions of Monocytes and Macrophages 1059

and immunoregulatory molecules. Receptors involved in microbial rec- resistance to viral infection and in cytosolic stress. Several well-known
ognition and innate immunity (e.g., cluster of differentiation [CD]14), G-protein–coupled receptors (GPCRs), including the array of selec-
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phagocytosis (e.g., FcR, CR), secretory, and killing mechanisms are tive, shared, even redundant chemokine receptors, β-adrenergic recep-
described, as are cytokine production and responses. Intracellular granule tors, and others contribute to the regulation of directed migration and
contents of monocytes include myeloperoxidase (MPO) and lysozyme, other cellular functions (Table 67–5). 96,97 In addition, a newly defined
although these are less studied than in neutrophils. family of GPCR with large extracellular domains, includes myeloid-re-
stricted members of the epidermal growth factor–seven transmem-
MOTILITY OF MONOCYTES brane (EGF-TM7) subfamily with multiple EGF (epidermal growth
AND MACROPHAGES factor) repeats. EMR2 (epidermal growth factor–like module con-
taining mucin-like hormone receptor–like 2) and CD97, structurally
An effective monocyte response to infection is predicated upon the related to the F4/80 antigen marker discussed in Chap. 68, likely sup-
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ability to migrate and accumulate at sites of inflammation and infec- port additional important monocyte functions. Their ligands include
tion. Monocytes are capable of both random and directed movement. complement regulatory molecules (CD55, associated with paroxysmal
Random migration is nondirected movement that occurs in the absence nocturnal hemoglobinuria; Chap. 40) and chondroitin sulphate B, a
of attracting substances. Directed movement, as a result of chemotaxis, matrix component. EMR2 expression on myeloid cells is upregulated
refers to monocyte migration that occurs in response to soluble factors by septic shock, its ligation on neutrophils potentiates a range of cellular
or stimuli and that is mediated by different types of receptors on phago- responses.
cyte cell surfaces. A number of different methods have been used to The roles of phosphoinositide metabolism, diacylglycerol gen-
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study macrophage movement both in vivo and in vitro. 92 eration, calcium fluxes, and phosphorylation/dephosphorylation in
Monocytes and macrophages are unusual among hematopoietic regulating actin assembly have been studied in human and mouse
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cells in that they are motile (ameboid type), migratory, yet capable of cells, using mainly neutrophils as a prototype. Genetic models of
sessile, “fixed” life in tissues as resident and more newly recruited cells. value for macrophage studies include src kinase knockout animals
Although not as motile as neutrophils, and more difficult to study in and the Wiskott-Aldrich syndrome. Small guanosine triphosphatases
physiologically relevant assays in vitro, they display lineage-specific, as (GTPases; rac, rho, cdc42) have been implicated in diverse myeloid
well as shared, yet distinct properties with DCs, which can be consid- functions, including cell spreading and membrane ruffling. Specialized
ered as more motile, less-adherent cells specialized for antigen capture adhesion structures that deserve further study in macrophages include
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and delivery to naïve and primed lymphocytes. They also share recep- focal adhesion, podocyte formation (particularly prominent in osteo-
tors and cytoskeletal properties with fibroblasts. Apart from diapedesis clasts) and possible participation in tight junctions; hemiconnexons
in response to endothelial and extravascular signals, monocytes and have been reported in macrophages in marrow stroma. CR3 contrib-
their progeny display polarization and specialized adhesion structures, utes to divalent cation-dependent adhesion of monocytes and mac-
most evident in the tight seal of osteoclasts to bone surfaces, so as to rophages to artificial, serum-coated substrates, such as bacteriologic
localize secretion of powerful catabolic products. plastic and the class A SR and MARCO (see “Non–Toll-Like, Nonopsonic
Adhesion is a defining event in the differentiation of monocytes, Receptors” above), which mediate divalent cation-independent adhe-
profoundly influencing the organization of the cell, its plasma mem- sion to serum-coated tissue culture plastic in vitro. However, the basis
brane, cytoplasm, and nuclear transcription machinery, as well as reg- of the remarkable, even unique, protease-resistant adhesion of mac-
ulating posttranslational modification of the proteome. Monocytes rophages to foreign materials remains mysterious. Improved imag-
express diverse integrins, implicated in outside-in as well as inside-out ing studies, combined with genetic manipulations, will bring further
signaling. Particularly important are the β -integrin heterodimers, insights into the regulation of monocyte/macrophage adhesion and
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2
restricted to myeloid cells, as opposed to β and β integrins shared with migration in vivo.
3
1
mesenchymal and other cells. The β integrins, lymphocyte function–
2
associated antigen (LFA)-1 (CD11a/CD18), CR3 (CD11b/CD18), and
CD11c/CD18, have been of great value in studies of monocyte/mac- INTERACTION WITH COAGULATION CASCADE
rophage adhesion. Inhibitory and stimulatory monoclonal antibodies Monocytes and resident macrophages line the sinusoids of liver (Kupffer
have been generated, and rare inborn errors of metabolism, such as the cells) and spleen and readily recognize activated platelets, binding them
leukocyte adhesion deficiency syndrome, caused by a genetic deficiency for clearance and destruction. In addition, monocytes produce potent
of the common β chain, result in defective myeloid cell recruitment to procoagulants, such as tissue factor, initiating a clotting cascade which,
2
inflammatory stimuli. if dysregulated, can lead to diffuse intravascular coagulation during sep-
The well-known sequence paradigm of rolling (mediated by tic shock. Following injury and inflammation, monocytes/macrophages
L-selectin), more stable adhesion (mediated by β integrins), and produce urokinase, to generate plasmin, in concert with endothelial
2
diapedesis has been extensively studied in neutrophils (Chap. 19), cell-derived tissue plasminogen activator. Macrophage production of
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and is thought to be similar for monocyte recruitment in response urokinase is regulated by phagocytic and other stimuli, and the active
to chemokines, as described in Chap. 68. Monocyte-specific and con- enzyme can bind to receptors (urokinase plasminogen activator recep-
stitutive migration through different tissue compartments (marrow, tor) on the cell surface in a complex interaction with protease–anti-
blood, tissues) are still poorly understood. An unresolved question is protease complexes, thus localizing fibrinolysis, which is important in
whether circulating monocytes are already “bar coded” for entry to wound repair.
special tissues, such as the CNS, or whether cells enter tissues stochas- The nature and source of the lipid tissue factor produced by mono-
tically from blood. cytes is not well characterized. The cells also produce a complex mix of
The control of monocyte motility in relation to chemotaxis contin- lipid metabolites, consisting of labile prostaglandins, leukotrienes, and
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ues to be studied. In particular, the energetics and role of mitochondria thromboxanes, by utilization of arachidonate-derived precursors and
in aerobic and hypoxic conditions deserve further study. Mitochondria substrates for phospholipase and cyclooxygenase-processing enzymes,
are prominent in DCs and play a wider role than anticipated in innate among others.

Kaushansky_chapter 67_p1043-1074.indd 1059 9/21/15 10:43 AM