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1054 Part VIII: Monocytes and Macrophages Chapter 67: Structure, Receptors, and Functions of Monocytes and Macrophages 1055

macrophages with immune complexes results in cell “activation,” has begun to offer agents to manipulate TLR signaling in humans. The
with an increase in phagocytosis, superoxide production, and pros- discovery of inborn errors, such as the interleukin receptor–associated
taglandin and leukotriene release. kinase (IRAK)-4 deficiency, and the role of toll-interleukin receptor
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adaptor protein (TIRAP) function in Plasmodium falciparum infec-
Complement Receptors tion, for example, have illustrated their role in human disease. Several
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Activation of the complement system results in liberation of numerous concepts have emerged. From the original studies on LPS recogni-
ligands that bind to specific receptors on mononuclear phagocytes. tion and signaling by the multiprotein complex formed by CD14, LPS
Four receptors that bind fragments of the complement component C3 binding protein, and MD2, and the clarification of the distinct adaptor
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have been identified (see Fig. 67–9). Complement receptor (CR) 1 pathways (MyD88 [myeloid differentiation factor 88], TIRAP/MAL
(or CD35) binds dimeric C3bi and is found on both monocytes and [MyD88 adaptor-like], TRIF [TIR domain-containing adaptor inducing
macrophages. CR3 (or CD11b) binds the complement fragment C3b. interferon (IFN)-β], and TRAM [TRIF-related adaptor molecule]), the
CR3 is a heterodimeric glycoprotein that is composed of two noncova- recognition and sensing of TLR ligands have become clear. The tertiary
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lently linked polypeptides. The α chain of the polypeptide has an Mr of structure of TLR4 has been reported. TLRs are expressed either on the
185,000, and the β subunit has an Mr of 95,000. This receptor and the plasma membrane of myeloid and other cells, or within the vacuole,
leukocyte antigens lymphocyte function–associated antigen (CD11a) especially in the case of TLRs 3, 7, and 9, which are implicated in viral
and alpha-X integrin chain (CD11c) compose a family of heterodi- nucleic acid recognition. Crosstalk among nuclear factor (NF) κB, IFN,
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mers that share a common β subunit (CD18). This family is desig- and mitogen-activated protein kinase (MAPK) kinase pathways has also
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nated the leukocyte integrin (β ) subfamily. These heterodimers are become apparent. TLRs collaborate with other recognition receptors,
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involved in cell–cell interactions, including leukocyte trafficking into such as dectin-1. Furthermore, a role has been proposed for TLR signal-
the tissues, binding of opsonized particles and plasma proteins, and ing in nontranscriptional activities, such as the kinetics of phagosome
attachment to various substrates. They also may modulate intercellu- maturation in macrophages. 59
lar adhesion. Elimination of the integrin β subunit causes leukocyte
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adhesion deficiency. 44 Non–Toll-Like, Nonopsonic Receptors
The classical opsonins, which promote the uptake of particles, are The study of lectins and SRs has lagged behind that of the above recep-
antibody, IgG complexed with antigens, and complement, activated by tors, but is gaining ground, documenting receptor expression and lig-
the classical pathway (antibody-dependent IgM or IgG) or recognized ands, mainly in mouse models of inflammation and infection. 35,60,61
directly via the lectin-carbohydrate–stimulated alternative pathway. Fc These receptors are present on macrophages and DCs, and variably
and CRs are heterogeneous in structure, expression, and function, on monocytes and neutrophils. They are implicated in the recogni-
activating or inhibiting macrophage responses, 45,46 as illustrated in tion and uptake of microbial and host ligands, and vary in their abil-
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Fig. 67–9. Other opsonins include fibronectin and milk-fat globulin. ity to activate host defense functions. Figure 67–11 and Table 67–3
Through their expression of various opsonic receptors, monocytes, illustrate the functional attributes of these receptor systems. The
macrophages, and DCs perform versatile roles in innate and adaptive mannose receptor is mainly involved in endocytosis, with a predom-
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immunity, in antigen clearance and destruction, in autoimmunity, inant intracellular localization. 62,63 The multilectin mannose receptor
and in pathogenesis of a range of inflammatory and infectious disor- displays dual functions, contributing to the clearance of mannose-
ders. Genetic polymorphisms influence the expression and functions terminal lysosomal hydrolases and of neutrophil granule glycopro-
of FcRs in homeostasis and disease. Although prominent in host pro- teins such as MPO, as well as of hormones (e.g., thyroglobulin) and
tection, invading microorganisms may be able to exploit, even subvert exocrine secretion products (e.g., amylase). It plays a role in the cap-
these receptors to facilitate their entry and survival. Opsonic receptors ture and transport of mannose-terminal glycoproteins to targets in
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play an important role in clearance of hematopoietic cells, for exam- spleen (marginal metallophilic macrophages) and in lymph nodes
ple, antibody-coated platelets, giving rise to thrombocytopenia, and in (subcapsular sinus macrophages) that express sulfated receptors for
therapeutic antibody treatment, for example, to facilitate engraftment. its cysteine-rich domain. The outcome of such targeting is either
Antibody engineering has provided novel therapeutic agents to mini- silent disposal or, if combined with TLR stimulation, induction of an
mize undesirable consequences, such as cell activation. The initiation or immune response. In common with several other nonopsonic recep-
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avoidance of complement activation in particular controls an important tors, it can play dual, even opposing actions in host protection or in
effector pathway in tissue injury and repair. pathogenesis, as shown by ongoing studies in mice.
Dectin-1 is a lectin-like receptor that is widely expressed on mye-
Toll-Like Receptors loid cells, with a single immunoreceptor tyrosine-based activation motif
The family of TLRs, identified on macrophages in mammals, is a pat- (ITAM)–like motif in its cytoplasmic tail. It recognizes β glucans,
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tern-recognition receptor that bind structurally conserved molecules abundant in fungal walls, including bioactive zymosan particles, and
derived from microorganisms, including endotoxins (LPS) and viral has been implicated in innate resistance to fungal infection. Dectin-1
nucleic acids. TLRs are now considered key molecules responsible for activates syk and caspase activation and recruitment domain (CARD)-9,
alerting the immune system to the presence of microbial infections. For regulating various effector pathways such as TNF-α, leukotriene pro-
example, TLR4 is part of a recognition couple for LPS. Pathogen rec- duction, and T-helper (Th) 17 cell activation, with heterogeneity in
ognition by TLRs activates the innate immune system through the sig- responses by macrophages and DCs. Dectin-1 collaborates with TLR
naling pathway and provokes inflammatory responses, such as cytokine 2/6 in the response to zymosan. Other lectins expressed by macrophages
production. These are shown schematically in Fig. 67–10 to illustrate include sialic acid recognition molecules, Siglec-1 (sialoadhesin), an
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their diverse structures and signaling pathways. extended Ig superfamily plasma membrane protein implicated in cell–
The discovery of TLR has transformed the study of innate immu- cell interactions (Chap. 68 discusses a possible role in the hematopoietic
nity, inflammation, and adjuvant actions on APC. 51–53 Receptor struc- system).
tures, heterogeneity of expression, microbial and endogenous ligands, SRs are a diverse family of structurally unrelated, promiscuous
and signaling have been defined, and knowledge of their regulation receptors, with a predilection for polyanionic ligands, expressed by

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