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Keywords:

  • Innate immunity;
  • Macrophages;
  • Phagocytosis

Abstract

  1. Top of page
  2. Abstract
  3. Past
  4. Present
  5. Future
  6. Conclusion
  7. Acknowledgements
  8. Appendix

As we approach the centenary of Elie Metchnikoff's Nobel Prize (1908), it is opportune to reflect upon the history of macrophage immunobiology, take stock of current knowledge and anticipate questions for the future. Starting from his appreciation of phagocytosis as an important determinant of host defence against infection and injury, we have learned a great deal about the distribution of macrophages throughout the body, their heterogeneous phenotype and complex functions in tissue homeostasis as well as in innate and acquired immunity. Recent discoveries of Toll-like and other plasma membrane, vacuolar and cytosolic recognition molecules have brought the macrophage and closely related dendritic cells to the centre of immunologic attention, but many earlier discoveries of their cellular and molecular properties have laid a broader foundation to the appreciation of their remarkable plasticity and adaptability to local and systemic cues. Discoveries of pro-inflammatory mediators such as TNF and other secretory products have provided valuable insights into the role of macrophages in many acute and chronic disease processes, and led to the development of effective therapeutics. Much remains to be discovered regarding both their specific functions and by study of their general cellular properties, in vitro and in vivo.

Abbreviations:
ENU:

ethylnitrosourea

NOD:

nucleotide oligomerisation domain

TAM:

tumour-associated macrophages

Past

  1. Top of page
  2. Abstract
  3. Past
  4. Present
  5. Future
  6. Conclusion
  7. Acknowledgements
  8. Appendix

As a comparative zoologist, Metchnikoff (Fig. 1a) prefigured the more recent discovery that innate immunity in invertebrates has much in common with that in mammals. Macrophage-like cells are distributed from sites of production that vary somewhat across widely differing multicellular organisms, depending on the emergence of a circulatory system, while sharing many general features. Hallmarks of their specialised properties include proficient phagocytosis, motility and biosynthetic capacity, coupled to remarkably diverse patterns of gene expression. The early discovery of phagocytosis in starfish and interpretation of its broader significance, together with imaginative studies on cellular immunity to infection in vertebrates, brought Metchnikoff recognition, but also generated intense controversy regarding its importance in relation to humoral immunity, discovered by Paul Ehrlich, who shared the Nobel award 1. In the end, both were right, while not at the time able to recognise the interactions of antibodies and complement with macrophages. What is perhaps not as widely known is that earlier microscopic studies by other scientists recorded the process of phagocytosis 2, but we owe to Metchnikoff a substantial body of knowledge, mostly proven to be correct, if incomplete in detail.

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Figure 1. Scientists who have contributed to our knowledge of macrophages: (a) Elie Metchnikoff (1845–1916), (b) Zanvil Cohn (1926–1993), (c) George Mackaness (1924–2007), (d) Philip D'Arcy Hart (1900–2006), and (e) Charles A. Janeway, Jr (1943–2003). See text for details. Figures from personal collection or courtesy from Joe Brock, National Institute of Medical Research (Fig. 1d).

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Almroth Wright subsequently emphasised the importance of phagocytes (polymorphonuclear leukocytes, initially described as microphages) and of plasma/serum-dependent opsonisation (from the Greek, to prepare for eating) in resistance to infection, as popularised by George Bernard Shaw in his play, The Doctor's Dilemma 3. The remarkably efficient clearance functions of ‘fixed’ macrophages (tissue histiocytes) was well appreciated in the first half of the 20th century, giving rise to the concept of a ‘reticulo-endothelial system’ (RES), associated with Aschoff and many other investigators. By the late 1960s it seemed appropriate to Ralph van Furth 4 and his colleagues to adopt a different name for this pleomorphic, but distinctive family of cells, viz. the mononuclear phagocyte system (MPS). In spite of the subsequent improved characterisation of diverse cells arising from common progenitors and sharing differentiation antigen markers, there is still considerable confusion in categorising subpopulations of macrophages and myeloid-type dendritic cells (DC) in tissues. The discovery by Steinman and Cohn 5 in the 1970s, of the specialised ability of DC to present antigen to naive T lymphocytes, in association with major histocompatibility complex molecules, is another important milestone in the essential role of antigen-presenting cells (APC) in the adaptive immune response. While the history of DC falls outside the scope of the present discussion, I emphasise that they share many, though varied properties on the theme of macrophages, representing a further, probably irreversible stage of differentiation of a common lineage. In that sense, osteoclasts, multinucleated cells that are specialised to resorb living bone, represent an analogous offshoot.

During the decades following the 1960s there was considerable progress in defining the cell biology of macrophages, especially in murine cell culture models pioneered by Zanvil Cohn (Fig. 1b) and his collaborators 6. These studies benefited from developments in light and electron microscopy by Palade, Porter and DeDuve, correlating morphological with biochemical analysis. However, it proved difficult to fractionate subcellular organelles from macrophages, compared with studies on neutrophil granules and lysosomes. Apart from extensive heterogeneity and complexity of intracellular vacuolar compartments of macrophages, progress was hampered by the limited amounts of experimental material and depended on subsequent molecular amplification techniques. However, it was evident already that macrophages are extremely dynamic cells, with intensive membrane trafficking, fusion and fission associated with endocytosis, phagocytosis and ruffling. In an elegant series of experiments, Silverstein and his colleagues 7, 8 described the zipper model of Fc receptor-mediated phagocytosis in which sequential interactions between receptors and ligands guide extensions of macrophage pseudopodia along the circumference of a particle (Fig. 2). This mechanism is distinct from ‘sinking’ mechanisms subsequently described for complement receptors 9 and the ‘coiling’ mechanism for uptake of Legionella pneumophila10.

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Figure 2. Electron micrograph to illustrate extension of macrophage pseudopodia during engulfment of an IgG-opsonised sheep erythrocyte, by a zipper-type mechanism.

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The availability of tumour-derived cell lines, which retained some, but not all, specialised properties of primary macrophages, made it possible later to take advantage of monoclonal antibody and cDNA cloning techniques. The discovery of macrophage-specific growth factors such as M-CSF, also known as CSF-1 11, yielded insights into cell differentiation in vitro and in vivo, with detection of the first well-defined naturally occurring genetic mutant involving macrophages, the osteopetrotic mouse 12, which was viable since it retained some macrophage subpopulations, unlike the artificially generated lethal PU-1 knockout 13. Bone marrow culture-derived macrophages could be produced in liquid or semi-solid media, providing insights into growth, differentiation and function. Subsequent important advances were based on newly available molecular methods including the cloning of M-CSF, and of other growth factors, cytokines and chemokines. In particular, the discovery by Cerami and colleagues 14 of TNF, initially as a lipopolysaccharide (LPS)-induced product of macrophages, brought insights into its pleiotropic role in tissue and lipid catabolism and vascular targeting actions.

The use of antigen markers such as F4/80 in the mouse and CD68 in human as well as the mouse made it possible to identify diverse macrophage populations in all the organs of the body, reinforcing earlier definitions of macrophages in lympho-haematopoietic organs, gastrointestinal, pulmonary and urogenital tissues, as well as the nervous system and reproductive tract 15, 16. Studies on constitutive entry of monocytes into the central nervous system during development, and their differentiation into arborised microglia, were particularly helpful in identifying the remarkable ability of monocytes to adapt to their local microenvironment and to develop into unique types of macrophages. These observations exemplified their role in clearance of apoptotic neurons, and in tissue remodelling, also providing convenient experimental models to study reactivation of microglia following local injury and enhanced recruitment of monocytes from blood, after which recently recruited monocytes soon develop similar morphologic features to the initially resident microglia. In general, it is difficult to distinguish resident and newly recruited monocytes/macrophages in tissues by antigen marker analysis.

Such studies brought home the importance of resident macrophages, distributed during development and throughout adult life in the absence of inflammation, and their extensive local heterogeneity, e.g. in lung, liver and gut. Apart from sentinel and clearance functions, resident macrophages in tissues are able to initiate acute inflammatory and vascular changes through their close association with the microvasculature; they display very different turnover rates and poorly defined trophic functions, e.g. in the bone marrow and in endocrine organs, as well as the nervous system. The development of liposome-encapsulated clodronate (dichloromethylene diphosphonate) as a method to eliminate phagocytic cells in vivo facilitated studies on the role of macrophage subpopulations in physiological and pathological processes 17.

The importance of induced recruitment of monocytes to local sites during development and following injury and infection has been appreciated for some time, especially in the study of granuloma formation. Such monocytes differentiate into macrophages with altered effector properties, including the ability to release reactive oxygen and nitrogen metabolites. The early work of Mackaness 18 (Fig. 1c), North and their colleagues put the concept of macrophage activation on the map, using Listeria and Bacillus Calmette-Guérin (BCG) as model infectious agents. They showed that macrophage activation was antigen dependent, but relatively non-specific in the expression of effector functions. Important discoveries in mouse and man defined the role of interferon-γ (IFN-γ) as an immune-activating cytokine for macrophages 19 in their defence against mycobacteria, which have macrophages as their natural habitat; the identification of human inborn errors in IFN-γ and its receptors, as for interleukin (IL)-12, validated the importance of this pathway of ‘classical activation’ initially discovered in experimental animal models of disease 20. Similarly, studies with antibodies and genetic mutants of adhesion molecules, e.g. for leukocyte adhesion molecules such as the β2 integrins, brought major advances in our knowledge of myeloid cell recruitment and diapedesis 21; progress on the neutrophil respiratory burst, the NADPH-oxidase and chronic granulomatous disease shed light on monocyte recruitment and antimicrobial mechanisms. Classic experiments by D'Arcy Hart 22 (Fig. 1d) and colleagues described the inhibition of acidification in mycobacteria-containing vacuoles in macrophages, later shown to be associated with delayed maturation of phagosomes and inhibition of their fusion with lysosomes. Subsequently, discovery of the inducible nitric oxide synthase (iNOS) and its role in IFN-γ-activated mouse macrophages represented a major milestone 23.

Experimentally, the ready availability of peritoneal resident, inflammatory (elicited by a sterile intraperitoneal injection) and immune-activated macrophages (e.g. after injection of BCG) provided more readily available populations for phenotypic analysis in the mouse. Complex model systems were also developed to characterise macrophage populations recruited to lipids accumulating within major arterial walls during atherogenesis 24 and to solid tumours, some of which contain substantial numbers of tumour-associated macrophages (TAM) 25. Lipid-laden foamy macrophages are thought to play an important role in the development and instability of atherosclerotic plaques, and TAM contribute poorly defined trophic benefits to the establishment, vascularisation and expansion of tumours.

Finally, the characterisation of plasma membrane receptors for opsonins (antibody 26, complement 27), for non-opsonic receptors 28 and for linked signalling pathways that mediate engulfment, cytoskeletal reorganisation, signal transduction, activation of transcription, antimicrobial and secretory responses has achieved remarkable progress in recent decades. Milestones include the delineation of various activating and inhibitory Fc receptors, the role of complement receptors in phagocytosis as well as leukocyte recruitment, the discovery of an array of scavenger and lectin-like receptors implicated in innate immunity and lipid homeostasis, and above all, the discovery of Toll-like receptors (TLR). This followed from several strands of initially independent lines of enquiry: the long-standing interest in LPS responses in genetically susceptible or resistant mouse strains 29 and identification of CD14 as LPS receptor and LPS-binding protein (LBP), as well as an associated protein MD2 in LPS-induced responses; the concept of pattern recognition receptors and of costimulation by adjuvants proposed by Janeway 30 (Fig. 1e) and Medzhitov 31; and the discovery of Toll receptor involvement in antimicrobial peptide production and innate immunity in Drosophila32 by Hoffmann and his colleagues. The link with mammalian TLR 33 was soon made, followed by an explosion of molecular and genetic experiments, notably by Beutler's 34 and Akira's 35 groups. Studies on the distribution, ligands and functions of multiple TLR have transformed our knowledge of the link between sensing of microbial and other defined ligands, induction of NF-κB and other signalling pathways and the role of these diverse leucine-rich repeat structures and their cytoplasmic domains in channelling information through a restricted number of adaptor proteins 36. Links were established between microbial recognition and response pathways, culminating in altered gene expression and cytokine production, especially TNF 37. TLR were shown to be able to sample cargo within phagosomes 38, or to detect viral nucleic acids within endosomes. TLR were implicated in a range of inflammatory conditions, including systemic sepsis, and macrophages were shown to be important, although not unique, in TLR expression and function.

Although type I IFN was already well known in antiviral, autocrine and paracrine responses, further links were established with TLR recognition 39. RIG-1-like cytosolic and mitochondrial sensing systems were discovered and IFN responses implicated in antimicrobial as well as antiviral macrophage responses. Although the role of macrophages in innate responses to viruses has been somewhat neglected, there is no doubt that they play an important role in HIV transmission, persistence and in secondary immunodeficiency 40. Macrophages are also thought to play an essential role in Dengue virus infection and its enhancement by pre-existing antibody in neonates and adults 41, 42.

Another major intracellular sensing system, the nucleotide oligomerisation domain (NOD)-like (nacht-like) receptors, was discovered by several investigators 43. These bear a resemblance to disease resistance proteins in plants. Studies by Tschopp on inflammasomes and caspase activation and IL-1β production clarified earlier observations on IL-1 receptors, which share signalling components with TLR. Remarkably, these findings complemented human genetic studies on hyperinflammatory syndromes such as familial Mediterranean fever 44, providing mechanistic insights and new therapeutic opportunities. Another powerful impetus was the discovery of NOD2 as a cytosolic receptor for muramyl dipeptide, a breakdown product of microbial peptidoglycans 45, and its implication in Crohn's, an inflammatory bowel disease. The generation of such microbial wall products may involve degradation by enzymes such as lysozyme 46, known as a major secretory product of macrophages, neutrophils and Paneth cells. Inherited lysosomal storage disorders such as Gaucher's disease 47 also display a major macrophage involvement, contributing to altered local and systemic pathology.

Present

  1. Top of page
  2. Abstract
  3. Past
  4. Present
  5. Future
  6. Conclusion
  7. Acknowledgements
  8. Appendix

This highly selective account provides a background to describe some areas and issues of considerable current interest.

Heterogeneity of monocytes

The studies by Geissmann 48, Jung and their colleagues, using a fractalkine GFP knock-in strategy to define monocyte subsets in vivo, provided a catalyst to study differential entry of newly recruited, inflammatory cells and resident APC in tissues (Fig. 3). Their studies in the mouse complemented earlier studies with human monocyte subpopulations by Ziegler-Heitbrock 49. Related investigations include analysis of monocyte/macrophage subpopulations in the formation of atherogenic plaques, in the gut and in recruitment following skeletal muscle injury. Further analysis has led to the discovery of novel progenitors for monocytes and DC, and made it possible to follow their progeny in various organs 50. While promising, this approach has proved more difficult in the study of resident subpopulations, which turn over more slowly than recently recruited cells. Surprisingly, selected tissue populations such as Langerhans cells and alveolar macrophages in the adult turn over in situ and can be replaced from local sources, independent of other macrophage and DC subpopulations. Some tissue populations of macrophage-related cells, e.g. in the marginal zone of the spleen 51, have a distinctive phenotype, but with a poorly defined origin. Even more distinct are plasmacytoid DC, which express both myeloid and lymphoid markers, as well as the potent ability to produce type I IFN 52.

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Figure 3. Differentiation and distribution of mononuclear phagocytes. Distinct subpopulations of circulating monocytes are thought to give rise to resident tissue macrophages, DC and osteoclasts compared with cells recruited by an inflammatory or immunologic stimulus. Further phenotypic heterogeneity arises from microenvironmental stimuli such as cytokines and microbial products. See 78 for the expression of surface markers by monocytes in different species. CCR2CXCR3high cells have been shown also to go into inflamed tissue.

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A further level of heterogeneity arises from the effects of cytokines and other extrinsic stimuli in determining the phenotype of mature, activated macrophages (Fig. 4). Direct microbial recognition can trigger TLR pathways, but also result in enhanced expression of marker antigens such as the class A scavenger receptor, macrophage receptor collagenous (MARCO) 53. Classical activation by IFN-γ can potentiate the function of this innate, microbial phagocytic receptor, whilst also selectively altering the profile of expression of other genes. By contrast, an alternative activation pathway 54, 55 represents a distinct, reproducible signature of gene expression induced by IL-4 and IL-13 acting through a common plasma membrane receptor chain 56. Such macrophages are associated with allergic responses, parasitic infection and possibly humoral responses, rather than with cellular resistance to intracellular pathogens, as seen with IFN-γ.

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Figure 4. Recognition receptors, localisation and signalling pathways. Macrophages express many receptors that mediate their diverse functions. The receptors are located on the surface as well as in vacuolar compartments and the cytosol, thereby mediating recognition of extracellular and intracellular pathogens. The opsonic receptors include complement receptors (integrins) and Fc receptors (Ig superfamily). They function in phagocytosis and endocytosis of complement- or antibody-opsonised particles, respectively 26, 79. Fc receptors have either an inhibitory (contain an immunoreceptor tyrosine-based inhibition motif [ITIM]) or an activatory (contain an immunoreceptor tyrosine-based activation motif [ITAM]) effect on NF-κB induction 26, 79. NF-κB is a family of nuclear transcription factors that regulate production of pro-inflammatory mediators. Another group of phagocytic/endocytic surface receptors are the non-Toll-like receptors (NTLR), which include the family of scavenger receptors and the C-type lectins 58, 80. Non-opsonic surface receptors that do not mediate phagocytosis/endocytosis but are important sensors of bacteria, fungi and viruses are the Toll-like receptors (TLR) 81. Scavenger receptors including CD36, SREC and LOX-1 have been shown to collaborate with TLR to induce NF-κB and may also directly mediate NF-κB induction upon interaction with ligand. Ligand recognition by lectins induces NF-κB, both directly and in collaboration with TLR. TLR can induce both NF-κB and IFN-regulatory factors (IRF) via a signalling cascade mediated by the adaptor molecules MyD88 and TRIF. Some TLR are located within vacuoles and play a role in recognition of intracellular pathogens. Cytosolic viruses and bacterial products are recognised by the NOD-like receptors (NLR) and RIG-like helicases (RLH) 37. NLR induce NF-κB either directly or in collaboration with TLR. RLH either induce NF-κB and IRF via mediators that are located on the outer membrane of the mitochondria or induce caspase-1-mediated apoptosis via the adaptor molecule ASC. In addition to NF-κB and IRF induction, there are a multitude of other signalling pathways within macrophages which have been omitted for clarity. Abbreviations: ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; MyD88: myeloid differentiation primary response gene; NOD: nucleotide-binding oligomerisation domain; TRIF: TIR domain-containing adaptor inducing IFN-β. (Courtesy of Dr. Annette Plüddemann).

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The control of macrophage activation is mediated by cytokines such as IL-10 and TGF-β as well as by arachidonate metabolites [prostaglandin E2 (PGE2)] and glucocorticosteroids. The activation status of other mature macrophage populations, e.g. in adipose tissue, atherosclerotic lesions and tumours, is not well defined, but bears some similarities to the alternative activation phenotype. Paired activating and inhibitory surface receptors, e.g. with ITAM or ITIM cytoplasmic motifs, play a significant role in controlling the activation state of the macrophage (Fig. 4).

Microbial recognition and macrophage responses

Whilst the reductionist approach has identified a range of well-defined ligands and signal transduction pathways for TLR and non-TLR (Fig. 4), there is still little understanding of the differential transcriptional and secretory responses of macrophages following interaction with whole organisms and cellular targets. The mouse ethylnitrosourea (ENU) mutagenesis forward-genetic screens employed by Beutler and his associates to study macrophage effector responses have already yielded many new target genes 34, in addition to validating earlier discoveries 57. There are well-studied examples of receptor interactions, including synergy, e.g. in the recognition of yeasts by Dectin-1, the β-glucan receptor, and TLR2 58. Although many microbes induce pro-inflammatory and antimicrobial responses, others are able to evade or subvert such responses. Apoptotic cell uptake, mediated by a range of opsonic and non-opsonic receptors, induces an anti-inflammatory response, consistent with the need for safe clearance 59. There is considerable controversy regarding the role of TLR in regulating the kinetics of phagosome maturation 60, and also in the extent to which the endoplasmic reticulum might contribute 61 to formation of phagosomes; some intracellular pathogens are able to direct the composition of the phagosome membrane, to locate in immature phagosomes, and to recruit Golgi/ER membranes 62 and/or disrupt the phagosome membrane in order to enter the cytosol. In particular Listeria monocytogenes has proved a dramatic and effective agent to alter the intracellular dynamics of actin assembly after infection 63, 64. The complexity and dynamics of endosomal and other compartments involved in endocytosis and secretion need further study 65. The effects of IFN-γ-induced GTPases on cytosol/phagosome membrane function have recently been shown to play an important role in intracellular pathogen resistance and host survival 6668.

Mycobacteria-macrophage interactions continue to provide important insights into phagosome maturation, fusion with lysosomes and acidification. The role of mycobacterial lipids in these host-resistance mechanisms is still under scrutiny.

The previously neglected process of autophagy 69 is receiving considerable current attention, in view of its relevance to infection by intracellular pathogens and its recent implication as a significant candidate mutant gene in inflammatory bowel disease 70.

Future

  1. Top of page
  2. Abstract
  3. Past
  4. Present
  5. Future
  6. Conclusion
  7. Acknowledgements
  8. Appendix

As our knowledge of molecular and cellular pathways grows apace, it will be important to remember their integration into more complex functions, perhaps best studied by combining in vitro analyses with whole animal studies and by paying more attention to macrophage cell biology. Remarkable progress on imaging within the living host 71 has already been made by multi-photon, fluorescent and NMR studies, e.g. in studying the recruitment of monocytes/macrophages to atherosclerotic plaques in mouse and in man. Less accessible tissues pose a bigger problem, as does the level of resolution that can be achieved.

I have my own personal wish list, remembering half-forgotten studies of earlier times. Non-phagocytic contact-dependent interactions involving macrophages and other cells have not received sufficient attention, but their trophic activities could play an important role in haematopoiesis within the bone marrow stroma 72, in homeostasis within the neuro-endocrine system 15 and in the evolution of tumours 25, where TAM are able to promote malignancy as well as influencing tumour cell migration and metastasis. The possibility that surface contact-dependent interactions can contribute directly to cellular and antimicrobial cytoxicity, without antibody involvement or phagocytosis, should also be considered. The ability of macrophages to discriminate between altered host components, e.g. of virus-infected cells and tumours, and normal physiologic constituents remains poorly defined, in spite of recent progress in our characterisation of the multiplicity of surface receptors. The functions of macrophage membrane receptors and transporters have received relatively little attention, compared with studies in lymphocytes and epithelial cells. Tractable experimental models are available to explore the mechanisms of macrophage membrane functions during cell-cell fusion, phagocytosis, adhesion and infection, by utilising present-day genetic, cellular and molecular techniques. A diverse range of naturally occurring pathogens (viral, bacterial, fungal and parasitic) encountered by the host early in the course of infection, are able to exploit, subvert or exacerbate the innate immune response. Model organisms, e.g. zebra fish 73 and Drosophila74, and global screens, e.g. after ENU mutagenesis of mice 34 or in genome studies of human genetic diversity 70, make it possible to identify novel genes implicated in macrophage functions.

The role of macrophages in the repair process and the resolution of inflammation 75 is still very poorly understood, awaiting the development of better experimental models of chronic inflammation. Similarly, there are tantalising examples of macrophage involvement in immunologic privilege, peripheral tolerance 76 and autoimmunity, all of which require further study.

The recent interest in stem cell biology brings new opportunities for future macrophage research. Whilst it is already possible to produce macrophages and DC from mouse and human ES cells in vitro, it is a formidable challenge to replicate, under controlled conditions in cell culture, the extensive phenotypic heterogeneity of macrophages that is observed in vivo. This will require a much better understanding of the role of extracellular matrix, cellular contacts and soluble components, as well as identification of site-, stage- and activation state-specific markers.

Another highly complex challenge is to unravel the role of transcription factors, abundantly present in macrophages 77, in regulated gene expression, in vitro and in vivo. The experimental ability to conditionally and selectively ablate or enhance macrophage function in vivo has already made considerable progress, but antibodies directed against specific surface receptors and regulatory plasma membrane molecules also lend themselves to improved molecular engineering.

Overall, a major therapeutic goal remains to modulate macrophage subpopulations selectively within the living host, without compromising important functions, especially host resistance to infection.

Conclusion

  1. Top of page
  2. Abstract
  3. Past
  4. Present
  5. Future
  6. Conclusion
  7. Acknowledgements
  8. Appendix

The concept that has emerged over the past century suggests that macrophages represent an evolutionarily ancient, dispersed, homeostatic system, on a par with the nervous and endocrine systems. The mononuclear phagocyte system is flexible, dynamic and able to respond to physiologic stimuli as well as pathologic circumstances. Macrophages are essential for survival and provide an attractive target to manipulate the host, for both immunologic and metabolic purposes.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Past
  4. Present
  5. Future
  6. Conclusion
  7. Acknowledgements
  8. Appendix

I thank all members of my group, past and present, who have contributed to the ideas discussed in this essay. Special thanks to Dr. Annette Plüddemann and Christine Holt for help in preparing the manuscript. Research has been supported by the Medical Research Council and the Wellcome Trust.

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    WILEY-VCH

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    WILEY-VCH

Appendix

  1. Top of page
  2. Abstract
  3. Past
  4. Present
  5. Future
  6. Conclusion
  7. Acknowledgements
  8. Appendix

Conflict of interest: The author declares no financial or commercial conflicts of interest.