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Keywords:

  • Cytokines;
  • Inflammation;
  • Macrophages

Introduction

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

Phagocytes are the founding pillars of innate immunity 1 and, as such, have been the object of intense scrutiny in the past few years. Mononuclear phagocytes constitute a system characterised by considerable diversity. Indeed, two major themes have emerged in recent macrophage investigations: their heterogeneity in different tissue environments and phenotypic plasticity in various physiologic and pathologic states 2–5. Macrophages contribute to tissue homeostasis by the clearance of effete and injured host components and to defence against infection by phagocytosis and microbial killing. Their secretory activities are central to inflammation and its resolution;and it has been widely recognised that they are prominent in modified forms of inflammation such as atherosclerosis and cancer. Yet, many questions remain regarding the molecular basis of their role in pathogenesis and the identification of potential targets for therapeutic manipulation. The Viewpoints in this issue of the journal provide an overview of some of the central themes in macrophage research.

Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

The F4/80 antibody 6, developed 30 years ago, made it possible to identify macrophages in mouse tissues during development and in the normal adult, as well as in a range of disease models. While strongly expressed by many resident macrophages in haematopoietic and non-haematopoietic organs, including the nervous system, several macrophage populations lack this marker, e.g. marginal zone metallophils and osteoclasts, or express it only weakly, including myeloid DCs. The significance of F4/80 expression heterogeneity by resident macrophages remains unclear; recruited inflammatory macrophages express the marker more uniformly.

Structurally, the molecule belongs to a small family of EGF-TM7 adhesion receptors expressed on myeloid cells, including CD97 and EMR2, for which ligands have been detected in the extracellular matrix. These molecules contribute to the regulation of innate and acquired immune responses; their putative role in GPCR signalling has not been established.

F4/80 has been followed by a number of molecules associated with mononuclear phagocyte differentiation, subset composition and polarisation 2. Transcriptional profiling has contributed new candidate molecules. A major challenge rests now in translating these molecules into research tools and diagnostics.

Recognition and regulation

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

Considerable progress has been made in understanding the mechanisms involved in the regulation of macrophage responses initiated by recognition. Following acute inflammatory stimulation via TLRs and related receptors, the activation state of macrophages is inherently unstable and often transitions into a state of tolerance, characterised by diminished signalling, repressive chromatin modifications and an alternative gene expression programme 7. The paradigm presented in the Viewpoint by Ivashkiv 7 lends itself to further experimentation, not least in relation to the manner in which pathogens are able to manipulate the host pro-inflammatory response.

MicroRNAs act as an important level of regulation of phagocyte responses 8. LPS-induced miRNAs include miR-146a, miR-21 and miR155; pathogens such as hepatitis C virus exploit miR-122 to facilitate replication, providing a novel target for therapy. Intriguingly, the well-known 5q-myelodysplastic syndrome results in the loss of several miRNAs.

The study of the regulation of gene expression by transcription control 9 and of epigenetic control of macrophage polarisation 10 is in its infancy but promises to provide important insights into macrophage differentiation and activation. Chromatin status-mediated regulation of promoter activity and enhancers, together with repressors, controls basal and inducible gene expression in macrophages, which provides an excellent model for further research. Epigenetic control of M2, alternative activation of macrophages is mediated by Jmjd3, a H3K27-specific demethylase. Moreover, the members of the IRF family are implicated as critical target genes for the control of M2 activation 10, 11.

Diversity, location and functions

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

The intestine is one of the most intensively studied local environments, an environment where macrophage and dendritic cell heterogeneity are relevant to mucosal immunity, microbiome composition and epithelial integrity. Resident and inflammation-recruited cell populations are regulated by local inhibitory signals, including TGF-β, IL-10 and inhibitory receptors, such as SIRPα and CD200 12. The question of cell identity is a thorny one, depending on the isolation procedure and in situ phenotypic analysis, and Bain and Mowat 12 question some of the interpretations of the studies by others on recruitment of CX3CR1 fluorescently labelled cells.

Regulatory macrophages are a functionally distinct type of alternatively activated macrophage, especially with regard to IL-12/IL-10 expression 13. Such macrophages are proposed to be induced by a two-signal mechanism (immune complexes plus either TLR- or IL-1 receptor-signalling, for example), responsible for this special phenotype, which holds promise for therapy of auto-immune diseases in the nervous system, and elsewhere.

Resolution of inflammation

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

Resolution is a largely neglected aspect of the inflammatory response. The population dynamics of acute inflammatory macrophages in the peritoneal cavity during resolution is complex 14. A recent study 15 has revisited local turnover rather than monocyte recruitment as a mechanism sustaining phagocyte populations at specific sites (Langerhans cells) or in selected populations such as alternatively activated macrophages.

Experimental schistosomiasis is one of the best-studied models of Th2-directed granuloma formation; here macrophages play a key role in resistance to parasite infection, chronic inflammation and its sequelae, such as fibrosis 16.

Cardiovascular pathology and cancer

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

Macrophage recruitment and plasticity are key components of atherosclerosis and tumour development. Defective ‘efferocytosis’, phagocytic clearance of apoptotic cells in the vascular wall, impacts on plaque necrosis, stability and vulnerability to thrombo-embolism 17. Recruitment of monocyte subpopulations in atherosclerosis and tumours, in which macrophage protective responses can promote disease, intriguingly share similarities 18.

Indeed, tumour-associated macrophages (TAMs) are a key component of cancer-related inflammation 19, 20 and here several questions remain open. In particular, evidence indicates that pathways orchestrating TAM function 21–23 are diverse in tumours originating in different tissues and that there can be heterogeneity in mononuclear phagocytes in a given tumour 24, 25.

Concluding remarks

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

Mononuclear phagocytes are the subject of renewed interest both within and outside the immunological community. Their functional plasticity and heterogeneity is a key element in homeostatic functions and disease, impacting on diverse functions beyond immunity, including metabolism, tissue remodelling and repair. As emphasised in some of the contributions in this viewpoint series, there is a strong need to relate results in rodents to human monocytes and macrophages, if new knowledge is to be translated into innovative diagnostic and therapeutic strategies.

References

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

Supporting Information

  1. Top of page
  2. Introduction
  3. Macrophage markers: F4/80 and the EGF-TM7 family of adhesion receptors
  4. Recognition and regulation
  5. Diversity, location and functions
  6. Resolution of inflammation
  7. Cardiovascular pathology and cancer
  8. Concluding remarks
  9. Acknowledgements
  10. References
  11. Supporting Information

The complete Macrophage Viewpoint series is available at: http://onlinelibrary.wiley.com/doi/10.1002/eji.v41.9/issuetoc

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.