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  • Review Article
  • Published:

Monocyte and macrophage heterogeneity

Nature Reviews Immunology volume 5, pages 953–964 (2005)Cite this article

Key Points

  • Peripheral-blood monocytes show morphological, antigenic and functional heterogeneity.

  • Bone-marrow monocytes that are released into the circulation express distinct receptors for chemokines and adhesion molecules and are preferentially recruited to inflammatory lesions, where they can differentiate into macrophages or dendritic cells (DCs). These monocytes have high phagocytic activity, are known as 'inflammatory' monocytes and are identified by a CC-chemokine receptor 2 (CCR2)+ CX3C-chemokine receptor 1 (CX3CR1)lowLy6C+ phenotype in mice and a CD14hiCD16−CD64+CCR2+CX3CR1low phenotype in humans.

  • Cells that constitute the other main subset of monocytes, which seems to be derived from the inflammatory monocytes in peripheral blood, seem to enter tissues under steady-state conditions, where they can contribute to the replenishment of tissue-resident populations of macrophages and DCs. These cells have been called 'resident' monocytes, and one of the functional differences between these monocytes and inflammatory monocytes is that resident monocytes have greater accessory activity in mixed leukocyte reactions. They are identified by a CCR2−CX3CR1hiLy6C− phenotype in mice and a CD14+CD16+CD64−CX3CR1hi phenotype in humans.

  • An intermediate phenotype of monocyte has also been observed, and these cells might be developmental intermediates. Similar to inflammatory monocytes, they respond to pro-inflammatory cues, but they also have high stimulatory activity in T-cell-stimulation assays, similar to resident monocytes. They have been suggested to be a monocyte subset that is recruited to inflammatory lesions and is prone to differentiate into DCs. They are identified by an intermediate phenotype in mice (CCR2+CX3CR1midLy6Cmid) and might be present in humans as CD14+CD16+CD64+ monocytes.

  • Tissue-resident macrophage populations are replenished by a combination of local proliferation of precursors and recruitment of bone-marrow-derived precursors. In most cases, it has not been formally shown whether monocytes or specific lineage-committed precursors fulfil this role.

  • The mechanism of replenishment of tissue-resident populations is greatly influenced by the presence of inflammation or injury, because under these conditions, a greater dependence on circulating precursors is evident in model systems.

Abstract

Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.

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Figure 1: Development and function of monocyte subsets in mice.
Figure 2: Origins of mature cells in the periphery in adult mice.
Figure 3: Macrophage heterogeneity during inflammation.

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Authors and Affiliations

  1. Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK

    Siamon Gordon & Philip R. Taylor

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  1. Siamon Gordon
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Correspondence to Siamon Gordon.

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DATABASES

Entrez Gene

CCR2

CD14

CD16

CD43

CD62L

CD163

CX3CR1

Ly6C

Glossary

OSTEOCLAST

A multinucleate cell that resorbs bone.

AFFERENT LYMPHATIC VESSEL

A vessel that carries lymph into a lymph node.

MIXED LEUKOCYTE REACTION

A tissue-culture technique for testing T-cell reactivity. The proliferation of one population of T cells, induced by exposure to inactivated MHC-mismatched stimulator cells, is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.

CLODRONATE-LOADED LIPOSOME

A liposome that contains the drug dichloromethylene diphosphonate. These liposomes are ingested by macrophages, resulting in cell death.

DIL-LABELLED LIPOSOSOME

A liposome that is labelled with the fluorochrome Dil (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate). These liposomes are internalized by phagocytic cells, rendering the cells fluorescent.

PERITONEUM

The membrane that lines the abdominal cavity.

STERILE PERITONITIS

Inflammation of the peritoneum that is induced by sterile injection of an irritant, such as thioglycollate broth. This results in the sequential recruitment of granulocytes, monocytes and lymphocytes. It is widely used to study acute inflammation.

EFFERENT LYMPHATIC VESSEL

A vessel that carries lymph out of a lymph node.

PATTERN-RECOGNITION RECEPTOR

A type of receptor that binds conserved molecular structures that are found in pathogens. Examples include the mannose receptor, which binds terminally mannosylated and polymannosylated compounds, and Toll-like receptors, which are activated by various microbial products, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA.

SCAVENGER RECEPTOR

A cell-surface receptor that is involved in the internalization of selected polyanionic ligands, including modified low-density lipoproteins.

TINGIBLE-BODY MACROPHAGE

A type of macrophage that is present in the splenic white pulp and is involved in the clearance of apoptotic cells.

LAMINA PROPRIA

The connective tissue that underlies the epithelium of the gut mucosa. It contains various myeloid and lymphoid cells, including macrophages, dendritic cells, T cells and B cells.

LANGERHANS CELL

A professional antigen-presenting dendritic cell that is localized in the epidermal layer of the skin.

BONE-MARROW CHIMERA

An individual that has received a transplant of bone marrow from another individual.

PARABIOTIC MICE

Mice that share a circulatory system as a result of surgical connection.

GRANULOCYTE/MACROPHAGE COLONY-FORMING-UNIT PRECURSOR

(GM-CFU precursor). A committed precursor in haematopoietic tissues that can form granulocytes and macrophages in the presence of specific growth factors.

OSTEOPETROTIC MICE

(Mcsfop/Mcsfop mice). An inbred strain of mice that suffers from osteopetrosis (stony bones) as a result of deficient function of osteoclasts. The defect has been localized to the gene that encodes macrophage colony-stimulating factor (M-CSF; also known as CSF1).

ALVEOLAR PROTEINOSIS

A disease that is caused by accumulation of surfactant proteins in the alveoli.

MICROGLIAL CELL

A type of macrophage that is derived from bone marrow, arborized and present in the parenchyma of the central nervous system.

PERIVASCULAR MACROPHAGE

A type of macrophage that lines small blood vessels: for example, near the surface of the brain.

MENINGEAL MACROPHAGE

A type of macrophages that is present in the meninges (the three membranes that surround the brain).

CHOROID-PLEXUS MACROPHAGE

A type of macrophage that is present at the interface between the blood and the cerebrospinal fluid in the brain.

MARGINAL-ZONE MACROPHAGE

A type of macrophage that is present in the splenic marginal zone and is involved in the recognition and clearance of material, such as pathogen-derived material, from the splenic circulation.

METALLOPHILIC MACROPHAGE

A type of macrophage that surrounds the splenic white pulp, adjacent to the marginal sinus.

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Gordon, S., Taylor, P. Monocyte and macrophage heterogeneity. Nat Rev Immunol 5, 953–964 (2005). https://doi.org/10.1038/nri1733

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