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Protective and pathogenic functions of macrophage subsets

Key Points

  • Macrophages are highly heterogenous cells that can rapidly change their function in response to local microenvironmental signals.

  • Although distinct macrophage subsets with unique functional abilities have been described, it is generally believed that macrophages represent a spectrum of activated phenotypes rather than discrete stable subpopulations. They adopt context-dependent phenotypes that either promote or inhibit host antimicrobial defence, antitumour immune responses and inflammatory responses.

  • Macrophages ingest and kill pathogens and maintain healthy tissue by removing dead cells and debris.

  • Because macrophages must be selective of the cells and materials they phagocytose, they use pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), C-type lectin receptors, scavenger receptors, retinoic acid-inducible gene 1 (RIG1)-like helicase receptors (RLRs) and NOD-like receptors, to recognize signals associated with invading pathogens, foreign substances (for example, silica or asbestos), and dead or dying cells.

  • Various macrophage subsets with distinct immune functions have been described. Classically activated macrophages (M1 macrophages) mediate defence of the host from various bacteria, protozoa and viruses, and also mediate antitumour immune responses. Alternatively activated macrophages (M2 macrophages) have an anti-inflammatory function and regulate wound healing. 'Regulatory' macrophages can secrete large amounts of interleukin-10 (IL-10) in response to Fc receptor-γ ligation. Other, less-well-defined macrophage subsets include tumour-associated macrophages, which suppress antitumour immunity, and myeloid-derived suppressor cells.

  • Alternatively activated macrophages regulate tissue repair and suppress tissue-destructive M1 responses. They express immunoregulatory proteins such as IL-10, resistin-like molecule-α (RELMα), chitinase-like proteins and arginase 1 (ARG1), which have been shown to decrease the magnitude and duration of inflammatory responses and promote wound healing.

  • Inflammatory (M1) and suppressive (M2) macrophages are crucially involved in the initiation and resolution of immune responses. Thus, macrophages exhibit both protective and pathogenic roles in a wide range of autoimmune and inflammatory diseases.

  • Although murine M1- and M2-polarized macrophage subsets are relatively easy to distinguish on the basis of combinatorial gene expression profiles, the identification of equivalent subsets in humans has been less clear.

  • The regulation of macrophages in the tissues remains unclear. We also do not understand how homeostasis is restored after infection, how the response to damaged tissues is resolved and what mechanisms are involved in the layered hierarchy of macrophage activation in situ. Research is needed on mechanisms that regulate the plasticity and stability of macrophage populations in vivo. Identifying the transcription factors and epigenetic changes that control macrophage plasticity will advance the field.

Abstract

Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals. They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals. In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis. We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing. Finally, we briefly discuss the characterization of macrophage heterogeneity in humans.

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Figure 1: Tissue macrophages perform important homeostatic functions.
Figure 2: Inter-organ communication is required for macrophage recruitment.
Figure 3: In situ macrophage proliferation.
Figure 4: Distinct macrophage subsets regulate inflammation and wound healing.

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Acknowledgements

Work in P.J.M.'s laboratory is supported by The Hartwell Foundation, US National Institutes of Health (NIH) CORE grant P30 CA21765 and the American Lebanese Syrian Associated Charities. T.A.W. is supported by the Intramural Program of the US National Institute of Allergy and Infectious Diseases, NIH.

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Glossary

Mononuclear phagocytic system

This system consists of bone-marrow-derived cells (monocytes, macrophages and dendritic cells) that have different morphologies and are mainly responsible for phagocytosis, cytokine secretion and antigen presentation.

Phagocytosis

A process that is used by cells to internalize large particles, such as debris, apoptotic cells and pathogens, into phagosomes.

Osteoclasts

Multinucleated giant cells of the monocyte lineage that are responsible for bone resorption. Osteoclasts degrade bone matrix and solubilize calcium from bone. Defects in their differentiation and a decrease in their number lead to bone osteopetrosis. Conversely, an increase in their number or function induces bone osteoporosis, indicating that osteoclasts have a pivotal role in bone homeostasis.

Alveolar macrophages

Resident macrophages of the lung that are exposed to alveolar lumen and phagocytose inhaled particles (such as dust or allergens) and microorganisms.

Kupffer cells

Large, stellate- or pyramidal-shaped, specialized macrophages that line the sinusoidal vessels of the liver. They regulate local immune responses, and remove microbial particles, endotoxin and other noxious substances that penetrate the portal venous system.

Microglia

Phagocytic cells of myeloid origin that are involved in the innate immune response in the central nervous system. Microglia are considered to be the brain-resident macrophages.

M1 macrophages

A macrophage subset that is activated by Toll-like receptor ligands (such as lipopolysaccharide) and interferon-γ. M1 macrophages express pro-inflammatory cytokines and inducible nitric-oxide synthase, among others.

M2 macrophages

A macrophage subset that is stimulated by interleukin-4 (IL-4) or IL-13. M2 macrophages express arginase 1, the mannose receptor CD206 and the IL-4 receptor α-chain, among others.

Tumour-associated macrophages

(TAMS). An important component of the tumour microenvironment. These cells differentiate from circulating blood monocytes that have infiltrated tumours. They can have positive or negative effects on tumorigenesis (that is, tumour promotion or immunosurveillance, respectively).

Myeloid-derived suppressor cells

(MDSCs). A group of immature CD11b+GR1+ cells, which include precursors of macrophages, granulocytes, dendritic cells and myeloid cells. Through direct interactions and secreted components, they negatively regulate T cell function.

Opsonin molecules

Proteins that bind to the surface of a particle and enhance its uptake by a phagocyte. Opsonins include IgG and complement activation fragments (including C4b, C3b, iC3b, C3dg and C3d).

Sterile inflammation

Inflammation that occurs in the absence of any microorganisms, as a result of tissue damage. In a similar way to microbe-induced inflammation, sterile inflammation is marked by the recruitment of neutrophils and macrophages and the production of pro-inflammatory cytokines and chemokines.

Extracellular matrix

(ECM). Secreted products of many cell types that form an organized scaffold for cell support.

Inflammasome

A molecular complex of several proteins that upon assembly cleaves pro-interleukin-1, thereby producing active interleukin-1.

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Murray, P., Wynn, T. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 11, 723–737 (2011). https://doi.org/10.1038/nri3073

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