Plasma membrane receptors control macrophage activities such as growth, differentiation and activation, migration, recognition, endocytosis and secretion. They are therefore important in a wide range of physiological and pathological processes including host defence, inflammation and repair, involving all systems of the body including the arterial wall and nervous system. The versatile responsiveness of these cells to various stimuli depends on their ability to express a large repertoire of receptors, some restricted to macrophages and closely related cells, others common to many cell types.

This volume contains reviews of the macrophage receptors that are best characterized and deals with aspects of signal transduction and function of the actin cytoskeleton. Our introduction is designed to place these topics in perspective. We summarize features of constitutive and induced mononuclear phagocyte distribution within the body and consider receptor expression and macrophage responses in the context of cell heterogeneity associated with its complex life history. We classify receptors discussed in detail in other chapters, list ligand-binding properties that are not as well defined, and briefly review general features of receptor function in macrophages. An understanding of macrophage receptor biology should bring insights into the contribution of these cells to physiology and disease and result in an improved ability to manipulate activities within the mononuclear phagocyte system.

The first macrophage receptors to be identified were those for Fc fragments of immunoglobulins (FcR) (Berken & Benacerraf, 1966) and for cleavage products of the third component of complement (CR) (Lay & Nussenzweig, 1968). Over the past 20 years there has been a great deal of work on the role of these receptors in opsonin-mediated phagocytosis and cytotoxicity, notably by Rabinovitch, Silverstein, Cohn, Bianco, Michl, Griffin, Wright and Nathan. (For general reviews of mononuclear phagocytes see volumes edited by van Furth (1980, 1985) and for reviews of endocytosis see Silverstein et al. 1977 and Steinman et al. 1983.) The isolation of specific monoclonal antibodies (mAb) for an FcR by Unkeless (1979) and for CR3 by Springer et al. (1979) and Beller et al. (1982) initiated a period of receptor characterization. These studies defined the synthesis, turnover and function of the FcR, which was purified and reconstituted in artificial lipid bilayers (for reviews see Unkeless et al. 1981, 1988; Mellman et al. (1988) this volume). Recently three groups have isolated cDNA clones for FcR (Lewis et al. 1986; Ravetch et al. 1986; Hibbs et al. 1986), established that FcR are members of the immunoglobulin (Ig) superfamily (Williams, 1987) and begun to define the molecular basis of FcR heterogeneity. Receptors for C3 were also shown to be heterogeneous and CR3 was found to be part of a family of related leukocyte heterodimers (LFA/ Mac-1/pl50, 95) (Springer et al. 1984). These contain a common ß chain, which is homologous with the integrin family of adhesion receptors present also in non-haematopoietic cells such as fibroblasts (Hynes, 1987; Ruoslahti & Pierschbacher, 1987).

Over the past decade it has become clear that macrophages express specific receptors for many other ligands including carbohydrate structures (Stahl et al. 1976, 1978), growth factors (Guilbert & Stanley, 1980), lymphokines such as τ interferon, and for plasma proteins that transport and clear lipid, Fe2+ and proteinases. Molecular studies of these receptors are in progress. Receptors for transferrin and lipoproteins have been well studied in other cells, but it is not known if their structure in macrophages is identical. Sherr et al. (1985) and Sacca et al. (1986) recently discovered that a macrophage-specific growth factor receptor (CSF-1 R, c-fms) is the cellular counterpart of a viral oncogene (v-fms) and further studies have established a central role for these molecules in normal and aberrant growth of macrophages (reviewed by Rettenmier et al. (1988) this volume). Receptors restricted to tissue macrophages in bone marrow (Crocker & Gordon, 1986) enable macrophages to regulate growth and differentiation of other haematopoietic lineages and have brought home the importance of non-phagocytic cell-adhesion molecules in macrophage functions (reviewed by Crocker et al. (1988) this volume).

Lymphoid surface glycoproteins, which play a role in immune cellular interactions, can also be expressed by macrophages. These include class I and class II molecules of the major histocompatibility complex (MHC) and CD4 antigens (Crocker et al. 1987), potential receptors for human immunodeficiency virus (HIV) entry. The normal ligands and receptor-like functions of these recognition molecules have not been defined. It is likely that several surface glycoproteins collaborate to promote specific, stable adhesion between macrophages and other cells in both phagocytic and non-phagocytic interactions. Receptors for complement and carbohydrate structure (Ezekowitz et al. 1984) or for complement and immunoglobulin (Ehlenberger & Nussenzweig, 1977) can synergize in the binding and ingestion of microorganisms and other particulate ligands by macrophages, and receptor interactions with matrix components such as fibronectin further modulate phagocytosis (see Wright & Detmers (1988) this volume). However, we have little understanding of these complex receptor interactions or of the molecular and signalling mechanisms that determine the resultant responses of the macrophage.

To place the cellular and biochemical aspect of macrophage receptor biology in perspective it is necessary to appreciate the complex life history of macrophages and their resultant considerable heterogeneity.

Constitutive distribution of resident macrophages

Macrophages are normally present in many tissues of the mammalian host, including the central nervous system (CNS), endocrine organs, gut and kidney, in addition to their well-known distribution in liver (Kupffer cells), spleen and other haematopoietic and lymphoid tissues. (For reviews see Gordon, 1986; Perry & Gordon, 1988.) Most of the macrophages that are resident in adult tissues derive from blood monocytes and thus from progenitors in the bone marrow, although local production of cells may continue in sites such as spleen and lung (alveolar macrophages) in the absence of an overt inflammatory stimulus. Monocytes first invade many of these sites during development, as production shifts from yolk sac to foetal liver and then bone marrow, and contribute to tissue remodelling during organogenesis, e.g. during naturally occurring death of neurones and axons in the CNS (Perry et al. 1985). Recruitment from bone marrow continues throughout adult life at a relatively low level in the steady state, and can be considerably enhanced by infection or injury. Mature resident macrophages in tissues are relatively long-lived (weeks, rather than days) compared with cells transiently recruited in inflamed tissues, and perform ill-defined trophic and homeostatic functions within the host, rather than the cytocidal activities vital for immune defence (Gordon et al. 1986a).

Evidence for the constitutive, widespread migration of macrophages has come from immunocytochemical studies with appropriate macrophage-restricted mAb, which extended earlier morphological observations. In liver, skin, bone marrow and spleen, the phenotype in situ has been correlated with that of cells isolated from these organs. Unlike the loosely or non-adherent macrophages, which can be readily lavaged from alveolar spaces or serosal cavities, resident macrophages are often deeply embedded within tissues, thus requiring collagenase digestion for isolation, with care to avoid destruction of delicate plasma membrane processes (Crocker & Gordon, 1985). In the mouse, the macrophage-specific antigen (Ag) defined by a rat mAb, F4/80, has been particularly useful for the recognition of cells belonging to the mononuclear phagocyte system (MPS) (Gordon et al. l986b). The F4/80 epitope is present on a 160K (K = 103Mr) integral plasma membrane molecule of unknown function. The Ag is stable to perfusion-fixation of tissues with glutaraldehyde or paraformaldehyde and, because of its plasma membrane localization, immunocytochemistry has made it possible to define the extent of macrophage processes and of their contacts with adjacent cells. These features are illustrated in Figs 1-3, which bring out the characteristic stellate morphology of resident macrophages in different tissues.

Fig. 1.

F4/80 immunocytochemistry of resident and BCG-activated macrophages in sections of murine lymphohaematopoietic organs. All figures show brown peroxidase reaction product after glutaraldehyde-perfusion fixation and avidin-biotin-complex staining. Controls without F4/80 antibody were unlabelled throughout. For further details see Hume et al. (1983a). A. Bone marrow. Stellate stromal macrophages are found in haematopoietic cell clusters, associated with F4/80- cells of the myeloid and erythroid series. Occasional rounded monocytes are also F4/80+. B. Spleen. Intense staining of macrophages in red pulp, with little staining in white pulp except associated with penetrating vessel. C,D. Normal liver at higher (C) and (D) lower magnification shows sinus-lining F4/80+ Kupffer cells. Hepatic endothelium and hepatocytes are F4/80-. E,F. Liver containing granulomata of mainly F4/80+ activated macrophages at lower (E) and higher magnification (F). Occasional polymorphonuclear leukocytes (PMN) and T lymphocytes in lesions are F4/80-. Note F4/80+ Kupffer cells between granulomata and reactive macrophages in adjacent sinuses, reflecting increased traffic through organ (S. Rabinowitz, unpublished).

Fig. 1.

F4/80 immunocytochemistry of resident and BCG-activated macrophages in sections of murine lymphohaematopoietic organs. All figures show brown peroxidase reaction product after glutaraldehyde-perfusion fixation and avidin-biotin-complex staining. Controls without F4/80 antibody were unlabelled throughout. For further details see Hume et al. (1983a). A. Bone marrow. Stellate stromal macrophages are found in haematopoietic cell clusters, associated with F4/80- cells of the myeloid and erythroid series. Occasional rounded monocytes are also F4/80+. B. Spleen. Intense staining of macrophages in red pulp, with little staining in white pulp except associated with penetrating vessel. C,D. Normal liver at higher (C) and (D) lower magnification shows sinus-lining F4/80+ Kupffer cells. Hepatic endothelium and hepatocytes are F4/80-. E,F. Liver containing granulomata of mainly F4/80+ activated macrophages at lower (E) and higher magnification (F). Occasional polymorphonuclear leukocytes (PMN) and T lymphocytes in lesions are F4/80-. Note F4/80+ Kupffer cells between granulomata and reactive macrophages in adjacent sinuses, reflecting increased traffic through organ (S. Rabinowitz, unpublished).

F4/80+ macrophages are often associated with vascular endothelium or epithelium, in addition to their interstitial location. Thus, cells either line sinusoids as in liver (Fig. IC,D) or in the adrenal gland (Fig. 2E,F), or surround capillaries, as in the lamina propria of the gut (Fig. 2A) and in highly vascularized interstitium of the ovary at particular phases of the reproductive cycle (Fig. 2D). Macrophage plasma membrane processes lie beneath the basement membrane of renal medullary epithelium (Fig. 2B), or penetrate a simple epithelium, as in the choroid plexus (Fig. 3B) or the submaxillary gland (Fig. 3D). Cells are found in skin (Fig. 3C,E) and throughout the transitional epithelium of bladder (Fig. 3F). Extensively arborized macrophages can form regular arrays in the basal layer of murine epidermis (Langerhans cells) (Fig. 3C,E), in other stratified epithelia, e.g. oesophagus, cervix (Hume et al. 1984a) and within the plexiform layers of the retina (Fig. 3A). Processes of macrophages in bone marrow stroma (Fig. 1A) and in epidermis (Fig. 3C) make numerous contacts vyith neighbouring cells, which display a high rate of proliferation and turnover, a finding suggestive of growth regulation of haematopoietic and epithelial cells by the centrally located macrophages.

Fig. 2.

F4/80 labelling of macrophages in adult mouse tissues. A. Small intestine shows F4/80+ macrophages confined to lamina propria, closely surrounding capillaries which are distended by perfusion-fixation. B. Kidney. Stellate processes of macrophages lie beneath epithelium in renal medulla. C. Fallopian tube. Macrophage processes lie mainly beneath epithelium. D. Ovary. Numerous F4/80+ cells in highly vascularized interstitial tissue surrounding developing follicle. E,F. Adrenal gland. E. F4/80+ cells are prominent in outer cortex and at cortico-medullary junction. F. Outer cortex at higher magnification. Note network of macrophage processes between steroid-secreting cells (zona glomerulosa at left of picture), frequent association of labelled cells with capillaries and cells in inner cortex spread along the walls of radiating vascular sinuses. For further details see Hume & Gordon (1983); Hume et al. (1984b).

Fig. 2.

F4/80 labelling of macrophages in adult mouse tissues. A. Small intestine shows F4/80+ macrophages confined to lamina propria, closely surrounding capillaries which are distended by perfusion-fixation. B. Kidney. Stellate processes of macrophages lie beneath epithelium in renal medulla. C. Fallopian tube. Macrophage processes lie mainly beneath epithelium. D. Ovary. Numerous F4/80+ cells in highly vascularized interstitial tissue surrounding developing follicle. E,F. Adrenal gland. E. F4/80+ cells are prominent in outer cortex and at cortico-medullary junction. F. Outer cortex at higher magnification. Note network of macrophage processes between steroid-secreting cells (zona glomerulosa at left of picture), frequent association of labelled cells with capillaries and cells in inner cortex spread along the walls of radiating vascular sinuses. For further details see Hume & Gordon (1983); Hume et al. (1984b).

Fig. 3.

F4/80 labelling of microglia and macrophages associated with epithelia. A. Retina. Microglia extend fine F4/80+ crenellated processes in outer plexiform layer to form a mosaic pattern. B. Choroid plexus. F4/80+ macrophages are prominent beneath and among F4/80- epithelial cells and blood vessels. C. Skin. Striking pattern of epidermal F4/80+ Langerhans cells closely associated with groups of unlabelled keratinocytes, in horizontal thick section of ear. D. Submaxillary gland. Section shows F4/80+ processes of macrophages penetrating between cuboidal duct epithelial cells, and occasional interstitial macrophages. E. Skin. Langerhans cells in transverse section (compare C). Lacunae that separate F4/80+ cells and epidermal cells are artefacts of fixation. F. Bladder. F4/80+ processes extend throughout transitional epithelium. Cells in lamina propria often lie adjacent to capillaries. For further details see Hume et al. (1983a,b; 1984a).

Fig. 3.

F4/80 labelling of microglia and macrophages associated with epithelia. A. Retina. Microglia extend fine F4/80+ crenellated processes in outer plexiform layer to form a mosaic pattern. B. Choroid plexus. F4/80+ macrophages are prominent beneath and among F4/80- epithelial cells and blood vessels. C. Skin. Striking pattern of epidermal F4/80+ Langerhans cells closely associated with groups of unlabelled keratinocytes, in horizontal thick section of ear. D. Submaxillary gland. Section shows F4/80+ processes of macrophages penetrating between cuboidal duct epithelial cells, and occasional interstitial macrophages. E. Skin. Langerhans cells in transverse section (compare C). Lacunae that separate F4/80+ cells and epidermal cells are artefacts of fixation. F. Bladder. F4/80+ processes extend throughout transitional epithelium. Cells in lamina propria often lie adjacent to capillaries. For further details see Hume et al. (1983a,b; 1984a).

Studies have revealed F4/80+ macrophages in lymph nodes and the red pulp of spleen (Fig. IB), but no labelling is seen in the white pulp, a region associated with T lymphocytes. Similar observations have been made with several anti-macrophage mAb, but it is likely that F4/80- macrophages are also present in these areas, as judged by other Ag markers. Additional heterogeneity in macrophage phenotype has been observed in the marginal zone of spleen (Humphrey & Grennan, 1981). These findings are of interest because of the obscure lineage interrelationship between macrophages and other ‘accessory’ cells that play a role in the induction of immune responses, especially primary T cell activation (Steinman et al. 1986). Steinman-Cohn dendritic cells, veiled cells and interdigitating cells are F4/80-, are present in T cell regions and express novel Ag (Kraal et al. 1986). Langerhans cells share properties with these accessory cells and macrophages, but lose their F4/80 Ag when isolated from skin and acquire the ability to stimulate a mixed leukocyte reaction upon cultivation in vitro (Schuler & Steinman, 1985). The macrophage phenotype therefore varies depending on the microenvironment in which they are found and on the conditions of culture after cell isolation. Present evidence is that macrophages consist of a single lineage of bone-marrow-derived cells, which displays considerable heterogeneity as a result of regional differentiation and modulation, but which does not represent distinct subsets determined during development.

Induced recruitment and accumulation in tissues in response to injury

Macrophages are present at most portals of entry and body interfaces and are well placed to form a first line of defence. In skin, lung, liver and spleen they are often the first host cells encountered by an invading organism or antigen, and, by releasing various mediators, macrophages are able to initiate an acute inflammatory reaction before endothelial permeability is increased and circulating leukocytes are recruited to an extravascular site of inflammation. Macrophages can recognize many foreign substances directly, without the help of plasma opsonins such as antibody and complement. This general ability to discriminate non-self from normal self predates the evolution of antigen-specific immune responses and may be related to the cells’ ability to recognize effete or damaged cells. Whether macrophages are able to distinguish alterations induced by viral infection or malignant transformation of target cells is not yet clear.

If the resident, relatively quiescent macrophages found in most tissues cannot contain an invader, increased numbers of monocytes are recruited to the site of injury, together with other blood cells, especially polymorphonuclear leukocytes, and plasma-derived molecules. The inflammatory reaction results in enhanced production of myelomonocytic cells, their recruitment from the circulation and increased turnover in haematopoietic tissues and locally. Macrophages elicited in response to sterile stimuli such as thioglycollate broth differ from those induced by infectious and other agents such as Bacillé Calmette Guerin (BCG), which recruit and activate macrophages by antigen-specific T-lymphocyte-dependent mechanisms. Although the elicited or immunologically activated macrophages can be distinguished by their expression of MHC II antigens and differential cytotoxicity (Ezekowitz et al. 1981) both types of newly recruited macrophages display common induced activities. These include an enhanced ability to undergo a respiratory burst and to generate toxic oxygen products, and production of extracellular proteinase activities such as plasminogen activator (urokinase), elastase and collagenase, which contribute to fibrinolysis and connective tissue catabolism during tissue injury and repair (Gordon & Ezekowitz, 1985). Resident macrophages do not produce these secretory activities and, in the case of Kupffer cells and certain other tissue macrophage populations, may be unable to generate a respiratory burst (Ding & Nathan, 1988). Defence against rapidly proliferating organisms such as Listeria monocytogenes therefore depends on the ability of the host to recruit circulating monocytes rapidly to local sites of infection such as liver, where resident macrophages are unable to contain the infection (Lepay et al. 1985). Recruitment of monocytes after injury within the peripheral, but not the central, nervous system may contribute to differential degeneration and repair within these sites (Perry et al. 1985).

The defence capacity of resident and recruited macrophages is augmented by other elements of the immune response such as specific antibodies and complement, which mediate FcR- and CR-dependent uptake and destruction of targets. Antigen-stimulated CD4+ as well as CD8+ T lymphocytes produce lymphokines that activate macrophages, especially τ interferon, and haematopoietic growth factors such as interleukin-3 (IL-3), granulocyte macrophage colony stimulating factor (GM-CSF), IL-4 and IL-5 (Chervinski et al. 1987; Kelso & Gough, 1987; Yokota et al. 1988). T lymphocytes therefore increase the numbers of macrophages both in haematopoietic tissues and locally, prime their respiratory burst capacity and enhance their killing potential towards extracellular as well as intracellular pathogens. Recruited, activated macrophages accumulate in tissues within granulomatous foci after mycobacterial infection of liver (Fig. lE,F), or are diffusely distributed throughout haematopoietic organs, as in murine malaria (Lee et al. 1986). Unlike resident macrophages, which show considerable regional heterogeneity, elicited and immunologically activated macrophages display a similar phenotype in different sites. Heterogeneity in phenotype and receptor expression between recruited and resident macrophages can be ascribed to differences in cell maturity and their modulation by lymphokines and other regulating agents.

Not all responses to injury involve recruitment of both myeloid and monocytic cells and the manifestation of other typical features of inflammation. Monocytes/ macrophages accumulate in the arterial wall in atherosclerosis, in lymphohaemato-poietic and other tissues in other ‘metabolic’ or storage diseases, and in some malignant tumours in the absence of neutrophils and an obvious inflammatory response. Little is known about monocyte-restricted chemotactic agents or the properties of these more selectively recruited macrophages.

Overall, production, migration and distribution of macrophages in tissues is precisely controlled in the steady state and after injury, although the mechanisms involved are still poorly understood. Surface receptors play an important role in all these processes including macrophage responses to chemotactic and other stimuli, adhesion to vascular endothelium, migration through tissues, interactions with other cells and resultant modulation of effector functions.

Given the wide distribution of macrophages and variety of macrophage functions and potential ligands, it is perhaps not surprising that macrophages are able to express a remarkable array of plasma membrane receptors. Their classification cannot yet be based on molecular structure, but a preliminary categorization is shown in the accompanying tables, based on known structures (Table 1) or reported ligands and functions (Table 2). Macrophages express surface receptors of several superfamilies (Ig, integrin and a family of structurally related proteins that interact with C3b or C4b). In addition there are various lectin-like receptors on macrophages (Table 3), one of which, the mannosyl-fucosyl receptor (MFR), is related to a circulating acute-phase mannose-binding plasma protein produced by the liver (Ezekowitz et al. 1988). The enumeration of receptors is complicated by the existence of different receptors for the same ligand (e.g. Ig subclasses) or multiple ligands for the same receptor molecule (e.g. CR3). The Fc, CR and mannosyl-specific receptors are discussed elsewhere in this volume and other chapters give details of the CSF-1 receptor and lipoprotein receptors. The various ‘scavenger’ receptor activities, which mediate endocytosis of modified proteins (e.g. acetyl low density lipoprotein (LDL), ß very low density lipoprotein (ßVLDL), formaldehyde-albumin, advanced glycosylation end product (AGE) protein) need to be better defined biochemically to establish how many different receptor molecules of this type exist. Many of the other receptor activities listed are still poorly characterized and cellular assignments (mononuclear cells, different macrophages) and plasma membrane localization also need further refinement.

Table 1.

Macrophage plasma membrane receptors and glycoproteins structurally related to known superfamilies

Macrophage plasma membrane receptors and glycoproteins structurally related to known superfamilies
Macrophage plasma membrane receptors and glycoproteins structurally related to known superfamilies
Table 2.

Ligands reported to bind to macrophage plasma membrane receptors

Ligands reported to bind to macrophage plasma membrane receptors
Ligands reported to bind to macrophage plasma membrane receptors
Table 3.

Lectin-like macrophage receptors

Lectin-like macrophage receptors
Lectin-like macrophage receptors

Ligation of macrophage surface receptors induces responses as diverse as cell growth, chemotaxis, endocytosis and secretion. In the absence of structural information about all except a few macrophage membrane molecules, our present knowledge of receptor functions, signal transduction and alterations in macrophage gene expression remains superficial. We do not understand the role of receptor cross-linking and phosphorylation, or of association with clathrin (Aggeler & Werb, 1982) and other cytoskeletal proteins in membrane internalization, recycling and routing to endosomes and lysosomes. In this section we consider general features of receptor function, for the most part derived from studies with macrophages in cell culture.

Growth, differentiation and modulation

Although production and modulation of macrophages can occur in different compartments of the body, it is useful to consider them as linked processes. Studies with primary bone-marrow-derived macrophages, monocytes, peritoneal cells and macrophage-like lines in cell culture have revealed complex regulation of the macrophage phenotype by colony-stimulating factors (CSF-1, GM-CSF, IL-3, IL-4), lymphokines (τ interferon) and other modulators (glucocorticoids (Flower, 1980), vitamin D metabolites, retinoids). Specific plasma membrane and other receptors play an important role in determining the effects of these agents on macrophages. Interactions of CSF-1 with murine macrophages, and activation of murine macrophages and human monocytes by τ interferon have been investigated in most detail. Cytokines such as IL-1, tumour necrosis factor (TNF), GM-CSF, which can be induced in macrophages, also influence the properties of macrophages themselves. Other examples of possible autocrine regulation include transforming growth factor (TGF) ß and interferon α ß which deactivate macrophage responses such as the respiratory burst (Yoshida et al. 1988) and altered MFR expression (Ezekowitz et al. 1986). Growth, differentiation and activation involve multiple regulators, which synergize or oppose one another, and an altered response of the macrophages to extrinsic regulators during its differentiation. Thus macrophages become progressively more refractory to growth stimulation as the cells mature and the monocytic stage may be more readily activatable, e.g. for cytotoxicity, than more terminally differentiated macrophages. Although cytokines and lymphokines induce pleiotypic, overlapping responses in macrophages, their effects are distinct, indicating that macrophage genes are co-ordinately, but selectively, regulated by each receptor-ligand interaction.

Interaction of CSF-1 with its normal receptor (CSF-1R) has been studied by Guilbert & Stanley (1980) who have shown that receptor molecules of mature macrophages are rapidly down-regulated after binding pure ligand. The role of abnormal CSF-1 receptors in leukaemogenesis is reviewed elsewhere in this volume by Rettenmier and colleagues. Recent studies indicate that the human CSF-1R gene is located in a region of the long arm of chromosome 5 that also codes for CSF-1 and several other haematopoietic growth factors and that deletions of this region are often associated with haematopoietic dysplasia (Bunn, 1986).

In contrast with CSF-1, interferon τ inhibits macrophage growth and is a potent modulator of macrophage differentiation. It induces a variety of surface and secretory products, but down-regulates other macrophage activities, thus reproducing many of the features of macrophages activated by T lymphocyte products in vivo (Nathan, 1986). The effects of interferons on target cell gene expression are under intense study (Revel & Chebath, 1986), but the interactions of τ interferon with its plasma membrane receptors are still poorly understood. Receptors are present in low numbers on many cell types, unlike the CSF-1R which is macrophage-restricted.Differences have been reported between receptors for interferon on macrophages and other cells (Orchansky et al. 1986). The availability of pure ligand will facilitate further studies in this important area.

Cell-cell and cell-matrix interactions

It is only recently that we have begun to appreciate that macrophage adhesion to another cell does not inevitably result in phagocytosis or its extracellular destruction. Non-phagocytic adhesion is selective for different target cells and can be transient or relatively stable. As illustrated in two recently studied examples, macrophage receptors interact with endothelium during enhanced cell recruitment (Rosen & Gordon, 1987) and, within tissues, with haematopoietic cells in bone marrow and foetal liver (Crocker et al. (1988) this volume). The CR3 and other members of the leukocyte functional antigen (LFA) and integrin families play a role in endothelial and matrix adhesion of induced monocytes and neutrophils, whereas haemagglutinins expressed by resident stromal macrophages bind developing cells during haematopoiesis. Ligands for these adhesion receptors include iC3b and gangliosides, respectively, but other determinants induced on stimulated endothelial cells may contribute to leukocyte adhesion (Bevilacqua et al. 1987). Purified or genetically modified receptors expressed in non-macrophages (Qu et al. 1988) or in model membranes should help to define the mechanisms of adhesion and signalling of functional responses. Substratum and matrix molecules (fibronectin, laminin) profoundly influence macrophage adhesion, endocytosis and secretion. The receptors themselves and their interactions with other membrane molecules and the cytoskeleton presumably determine whether the macrophage ingests or destroys a bound target, rather than influence target cell activities by non-phagocytic trophic interactions. Further studies of receptor structure and functional modifications such as phosphorylation should clarify these differential cellular responses.

Endocytosis

Phagocytosis and receptor-mediated pinocytosis are hallmarks of the differentiated macrophage, which is able to bind and internalize a large range of particulate and soluble ligands efficiently and selectively. A great deal has been learnt concerning the role in this process of receptors for opsonins (Fc, CR1 and CR3) and of receptors that interact directly with other specific ligands such as sugar moieties. The mechanism of particle ingestion involves zipper-like interactions between ligands and receptors (Silverstein et al. 1977) and different receptors are able to synergize in phagocytosis (Wright & Silverstein, 1986). Continuous and induced endocytic activity in macrophages involves extensive membrane flow and recirculation (Steinman et al. 1983). The role of the cytoskeleton and other determinants of ingestion has only been partially defined (Silverstein et al. 1977).

The technique of receptor modulation devised by Michl et al. (1979, 1983a,b) made it possible to cap receptors from the surface of adherent macrophages in culture and study their role in phagocytic recognition. If macrophages are cultivated on a defined ligand such as immune complexes, FcRs are selectively redistributed to the adherent surface and cleared by endocytosis, with resultant loss of receptor activity. The possibility that other molecules can be made to co-cap with the receptor under study has not been fully explored, nor have the effects of modulation been determined on receptor biosynthesis and turnover, or on polarized secretion by macrophages adherent to a surface-bound ligand.

An example that illustrates the value of this procedure is the identification of receptors that permit intracellular parasites such as Leishmania to penetrate macrophages (Blackwell et al. 1985; Mosser & Edelson, 1985). In the presence of fresh serum, a source of complement-derived ligands, promastigotes (the flagellated form) activate the alternative pathway and enter macrophages via CR3; in the absence of an exogenous opsonin, the entry mechanism is less efficient, but still involves the CR3 acting in concert with other sugar-recognizing receptors such as the MFR (Blackwell et al. 1985) or AGE-R (Mosser et al. 1987). Intriguingly, macrophages themselves are able to secrete all the components of the alternative pathway, but whether CR3 itself functions by ‘local opsonization’ (Ezekowitz & Gordon, 1984) or by a direct adhesive epitope is not clear. Parasite molecules that can be recognized directly through their sugar structures and as ligands for CR3 have recently been identified (Russell & Wright, 1988). Similar phagocytic recognition mechanisms extend to other invading organisms such as Legionella pneumophila (M. A. Horwitz, personal communication) andHistoplasma capsulatum (Bullock & Wright, 1987) and by virtue of macrophage-specific expression of receptors accounts for tissue tropism of several infectious agents.

Of the events that follow internalization, we have some knowledge of receptor retrieval and sorting, but little insight into the mechanisms. Intracellular fusion between endosomes and lysosomes involves saltatory movements of organelles (D’Arcy-Hart et al. 1983) and selective membrane fusion. The role of valency in targeting FcR molecules and ligands to lysosomes has been described by Mellman and his colleagues (Ukkonen et al. 1986). Together with studies of endosome acidification (Okhuma & Poole, 1981), this work has important implications for entry and neutralization of enveloped viruses in macrophages (Porterfield, 1986). Intracellular organisms such as Toxoplasma (Jones & Hirsch, 1972), Legionella (Horwitz, 1986), Trypanosoma cruzi (Nogueira etal. 1980) AND Leishmania (RabinovitchetaZ. 1986) are able to evade macrophage defence mechanisms during or after entry and provide fascinating insights into vacuolar function. They can avoid triggering a respiratory burst (Wilson et al. 1980), enter by an unusual coiling mechanism (Horwitz, 1986), inhibit acidification of phagosomes (Horwitz, 1987), prevent phagosome—lysosome fusion or disrupt phagosome membranes, remaining within or escaping from phagosomes or phagolysosomes into the cytosol.

Secretory responses and biosynthesis of effector molecules

It has now been recognized for some time that macrophages are not only ‘professional’ phagocytes, but also major secretory cells able to generate a large variety of products, which contribute to extracellular functions of macrophages in inflammation and the steady state (Gordon, 1978). Recent compilations of macrophage products are given in the reviews by Nathan (1987) and Werb et al. (1986). Ligation of surface receptors plays an important role in triggering exocytosis and release of membrane-derived and other molecules, and modulates macrophage biosynthetic activities and effector functions. Release of reactive oxygen metabolites, arachidonates and neutral proteinases can be triggered via FcR (Johnston et al. 1976; Nathan, 1980) or MFR (Berton & Gordon, 1983), especially by endocytic stimuli (immune complexes, zymosan), although internalization of a particulate ligand is not required (Rouzer et al. 1980). The role of CR3 in triggering of secretion, acting alone or in combination with other receptors, is not clear (Wright & Silverstein, 1983; Yamamoto & Johnston, 1984; Aderem et al. 1985). Release of different products is independently regulated and also a function of macrophage heterogeneity. Signal transduction mechanisms have not been well studied in macrophages and some aspects are discussed by Aderem and by Yin & Hartwig in other chapters in this volume. Information on receptor structure and regulation of the genes involved in product formation may help us to understand the linkage between plasma membrane events and longer-term synthetic responses. It is curious that macrophages secrete several products that can themselves act as local opsonins (complement, fibronectin, macroglobulin), indicating a possible further link between secretion and endocytosis. Newly available probes for lysozyme (Chung etal. 1988), urokinase (Belin et al. 1985), ad-antitrypsin (Kurachi et al. 1987), complement proteins (Colten et al. 1986), GM-CSF (Gough et al. 1984), interleukin-1 (Lomedico et al. 1984) and TNF (Pennica et al. 1984; Fransen et. al. 1985) should clarify the mechanisms that control their production and release in macrophage trophic and cytotoxic activities.

The recruitment of resident and induced macrophage populations to tissues and the varied nature of their resultant local interactions are reflected in considerable heterogeneity in receptor expression. We are still a long way from understanding the mechanisms that control expression of macrophage plasma membrane receptors in vivo or in vitro. Studies of FcR, CR3, MFR and CSF-1R have illustrated some of the factors that modulate their activity. Known modulating ligands include various colony stimulating factors and lymphokines, glucocorticosteroids and extracellular matrix proteins, which selectively alter the receptor phenotype of macrophages. For example, cell activation by BCG infection in vivo or τ interferon in cell culture enhances expression of murine FcR for Ig2a ligands (Ezekowitz et al. 1983), but down-regulates FcR for IgGl/2b ligands and also MFR activity (Ezekowitz & Gordon, 1984). This can be counteracted in part by dexamethasone, an inducer of MFR (Mokoena & Gordon, 1985). Future studies on receptor genes and their expression should clarify molecular mechanisms, but we also need to understand the synthesis, processing and transport of these molecules to and from the macrophage plasma membrane, as well as receptor modification and turnover (Mellman et al. 1983). Retention of differentiated trait function in cell culture makes the macrophage an attractive model to study cellular and molecular mechanisms involved in receptor expression.

There are other intriguing examples of heterogeneous macrophage receptor expression in vivo. We lack quantitative data on receptor numbers and on surface or intracellular distribution of macrophage receptors within the animal, but these can be determined by in situ methods and with freshly isolated cells. CR3 antigen is undetectable in murine Kupffer cells and other macrophages embedded in lympho-haematopoietic tissues, but receptor epitopes are present on monocytes, peritoneal macrophages and microglia. Another member of the LFA family, the p150,95 molecule is readily detectable on human tissue macrophages, which also lack CR3 antigen (Hogg et al. 1986). In mice, in contrast with resident Kupffer cells, macrophages recruited to liver by infection with Plasmodium yoelii or Listeria monocytogenes express high levels of CR3. These studies indicate that cell maturity and the local microenvironment influence macrophage CR3, although the mechanism of its regulation in vivo is not known. One possibility is that the CR3 plays a role in adhesion of circulating monocytes to liver sinusoids and is then selectively down-regulated by local interactions that do not occur elsewhere, e.g. in the CNS. Although less well documented, there is also developmental regulation of FcR expression and human tissue macrophages express FcR antigens which are not present on monocytes (Unkeless, 1986).

The importance of the CNS as a unique local microenvironment determining macrophage phenotype and receptor expression has been shown further in studies with CD4 antigens versus CR3 and FcR (Perry & Gordon, 1987). There is selective down-regulation of CD4 antigens on microglia within the blood-brain barrier, compared with elsewhere in the nervous system. These difference may be brought about by differential exposure to circulating plasma proteins or by local interactions with distinct populations of neuroglia. The receptors of macrophages within the brain are also modulated after monocyte entry and migration, during differentiation into mature microglia, reactivation of microglia, and enhanced monocyte recruitment after local injury or inflammation.

The human leukocyte adhesion deficiency syndrome in which CR3, LFA-1 and p150,95 molecules are all deficient has provided an informative inborn error to study macrophage receptor dysfunction in vivo (Springer & Anderson, 1986). A recent example of the use of transgenic mice to study macrophage growth factor overexpression (Langer al. 1987) shows that experimental models can be developed to manipulate macrophage receptor expression in vivo. Macrophage FcR expression can also be influenced within an intact rodent or primate by injection of a specific anti-receptormAb (Kurlander et al. 1984; Clarkson et al. 1986). This results in prolonged loss (lasting weeks) of receptor function in hepatic macrophages as judged by clearance studies. Administration of antibodies directed against a CR3 epitope (5C6) different from Mac-1 results in a more transient (lasting days), but marked loss of the ability of myelomonocytic cells to adhere to endothelium and enter an inflammatory site (Rosen & Gordon, 1987). Another way to deplete macrophages or modulate receptor activity is to target toxic lectins to macrophage populations by exploiting their known receptor activities, e.g. for sugar-specific (Simmons et al. 1986, 1987) or FcR-mediated uptake (Refnes & Munthe-Kaas, 1976). Restricted tissue expression and ready internalization make the endocytic receptors of macrophages attractive targets for such experiments.

Our inability to detect receptor activity in a particular macrophage population (e.g. CR3 on Kupffer cells) can be due to its absence or to blockade by bound ligand. cDNA probes make it possible to determine by in situ hybridization whether the mRNA is present. The combined used of nucleic acid and mAb probes should clarify some of the mechanisms by which different macrophages vary expression of receptors in vivo.

Plasma membrane receptors play a major role in every aspect of the complex life history of the macrophage. Genetic and immunochemical probes and advances in receptor biochemistry have now made it possible to characterize and define the functions of known macrophage receptors, and to discover new receptor molecules involved in macrophage biology. Differential regulation of plasma membrane receptors on macrophage subpopulations normally present in different sites within the body, or on cells recruited during an inflammatory or degenerative process, should permit selective modulation of macrophage functions. Future progress will depend on integrated investigations of receptor structure and function in vitro and within the host.

Supported by the Medical Research Council, U.K., the Arthritis and Rheumatism Council (HR) and the Wellcome Trust (VHP). We thank Elwena Gregory and Pam Woodward for typing, Stan Buckingham and Cathy Lee for photography, Dr David Hume and Peter Tree for unpublished photomicrographs and Dr Genevieve Milon for helpful comments on the manuscript.

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