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Studying the mononuclear phagocyte system in the molecular age

Key Points

  • The study of animals with global knockouts of genes encoding various cytokines, cytokine receptors and transcription factors has been crucial for understanding the development and homeostatic requirements of monocytes, macrophages and dendritic cells.

  • Depletion models — such as those using clodronate liposomes or animals that express the diphtheria toxin receptor under the control of a myeloid cell-specific gene promoter — have allowed for inducible and more precise elimination of various mononuclear phagocyte populations.

  • Crossing mice that express Cre recombinase under the control of myeloid cell-specific promoters with animals that have 'floxed' genes has been used to achieve cell-type specific deletion of a particular gene.

  • Identifying myeloid promoters with improved specificity for particular mononuclear phagocyte populations will be crucial in order to more precisely dissect the different functions of particular populations.

  • Molecular profiling of specific mononuclear phagocyte populations will help to identify more specific promoters and candidate genes to analyse functionally.

  • The development of new humanized mouse models holds the promise of accelerating the study of the human mononuclear phagocyte compartment.

Abstract

The mononuclear phagocyte system (MPS) comprises monocytes, macrophages and dendritic cells. Tissue phagocytes share several cell surface markers, phagocytic capability and myeloid classification; however, the factors that regulate the differentiation, homeostasis and function of macrophages and dendritic cells remain largely unknown. The purpose of this manuscript is to review the tools that are currently available and those that are under development to study the origin and function of mononuclear phagocytes.

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Figure 1: Lineage of mononuclear phagocytes.

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Acknowledgements

A.C. is funded by a fellowship from the US National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (5F30HL099028-02). B.D.B. is supported by an NIH Pathfinder Award (DP2DK083052-01 and 1R56AI081741-01A1) and funding from the Juvenile Diabetes Research Foundation (17-2010-770). M.M. is supported by NIH grants CA112100, HL086899 and AI080884.

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Glossary

Monocytes

Monocytes are mononuclear phagocytes that circulate in the blood. Monocytes are thought to differentiate into macrophages and some dendritic cells in peripheral tissues. They consist of two subsets: classical monocytes and non-classical monocytes.

Macrophages

Macrophages are tissue-resident phagocytes that specialize in the capture and clearance of damaged cells. Macrophages also capture and clear microorganisms and secrete pro-inflammatory molecules in response to microbial infection, and thus have a crucial role in host defence.

Dendritic cells

(DCs). DCs are tissue-resident phagocytes that specialize in the presentation of antigens to T cells to promote immunity to foreign antigens and tolerance to self antigens.

Classical monocytes

(Also known as inflammatory monocytes). This subset of monocytes is important in innate immune protection against infectious pathogens. During infectious challenge, these cells produce pro-inflammatory cytokines and can give rise to TNF- and iNOS-producing (TIP) dendritic cells, which contribute to the development of adaptive immune responses. In mice, these monocytes are characterized by high-level expression of LY6C, CCR2 and L-selectin (CD62L). In humans, classical monocytes are CD14hiCD16.

Non-classical monocytes

This subset of monocytes patrols the blood circulation and has been shown to promote tissue healing. There is evidence that these cells are derived from classical monocytes and can give rise to tissue-resident macrophages. In mice, these cells are characterized by low-level expression of LY6C and high-level expression of CX3CR1, LFA1 and CD43. In humans, non-classical monocytes are CD14CD16+ or CD14lowCD16+.

Graft-versus-host disease

(GVHD). Tissue damage in a recipient of allogeneic tissue (usually a bone-marrow transplant) that results from the activity of donor cytotoxic T lymphocytes that recognize the tissues of the recipient as foreign. GVHD varies markedly in extent, but it can be life threatening in severe cases. Damage to the liver, skin and gut mucosa are common clinical manifestations.

Langerhans cells

Dendritic cells that inhabit the epidermis. They are best distinguished by their high-level expression of the C-type lectin receptor langerin and its associated Birbeck granules. In contrast to other dendritic cells, Langerhans cells self-renew locally and are not depleted by high doses of X-ray irradiation.

Cre recombinase

Cre is a site-specific recombinase that recognizes and binds specific DNA sequences known as loxP sites. Two loxP sites recombine in the presence of Cre, enabling excision of the intervening DNA sequence.

Dicer

Dicer is an endoribonuclease that cleaves double-stranded RNA and is important for processing pre-microRNAs.

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Chow, A., Brown, B. & Merad, M. Studying the mononuclear phagocyte system in the molecular age. Nat Rev Immunol 11, 788–798 (2011). https://doi.org/10.1038/nri3087

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