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Alternative activation of macrophages

Key Points

  • Macrophages are a heterogeneous population of resident and recruited cells that are found in all organs and are involved in tissue homeostasis and defence of the host.

  • The cells express a wide range of surface receptors, which mediate their recognition of endogenous and microbial ligands.

  • Activation of macrophages by surface ligands and cytokines induces a spectrum of pro- and anti-inflammatory states, which are responsible for immune activation and deactivation.

  • The T helper 2 (TH2) cytokines interleukin-4 (IL-4) and IL-13 induce a characteristic, stereotypical, 'alternative' activation state of macrophages that is distinct from the 'classical' TH1-type activation by interferon-γ and deactivation by IL-10 and transforming growth factor-β.

  • The effects of IL-4 and IL-13 on macrophages contribute to clearance, presentation of antigens and repair in allergic immune reactions and parasite-induced granuloma formation.

  • Useful markers of alternative macrophage activation include induction of expression of the mannose receptor, MHC class II molecules and selected chemokines, as well as new gene products that have been discovered by gene-expression studies.

  • In this review, I argue for a more limited definition of alternative activation by IL-4 and IL-13, which act through a common receptor subunit, and I distinguish this form of activation from other forms of immunomodulation.

  • This model lends itself to further study of macrophages by gene profiling and proteomics, and it might become extended to a range of other forms of modified immune responses, with potential therapeutic benefits.

Abstract

The classical pathway of interferon-γ-dependent activation of macrophages by T helper 1 (TH1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.

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Figure 1: Innate and acquired immune activation of macrophages.
Figure 2: Differential utilization of L-arginine by activated macrophages.

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Acknowledgements

Work in my laboratory is supported by the Medical Research Council, UK, The Wellcome Trust, the Arthritis Research Campaign and the British Heart Foundation. I thank C. Holt for invaluable help with the preparation of this manuscript, and many colleagues for helpful discussions.

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DATABASES

LocusLink

ApoE

β-glucan receptor

CCL2

CCL3

CCL4

CCL5

CCL17

CCL18

CCL22

CCR1

CCR2

CCR4

CCR5

CD31

CD32

CD47

CXCL1

CXCL2

CXCL9

CXCL10

CXCR1

CXCR2

EMR1

FIZZ1

GATA3

GM-CSF

IDO

IFN-γ

IL-1

IL-3

IL-4

IL-6

IL-9

IL-10

IL-12

IL-13

IL-17

IL-18

IL-25

KIT

mannose receptor

M-CSF

NOS2

PPARγ

PU.1

SOCS3

SR-A

STAT3

STAT6

TGF-β

TNF

VEGF

Ym1

Glossary

CRE–LOX TECHNOLOGY

Cre is a site-specific recombinase that recognizes and binds specific sites known as loxP. Two loxP sites recombine in the presence of Cre, allowing DNA that is cloned between two such sites to be removed by Cre-mediated recombination.

CHROMATIN IMMUNOPRECIPITATION

(ChIP). The use of antibodies specific for transcription factors to precipitate nucleic-acid sequences from chromatin for amplification.

SUPPRESSION SUBTRACTIVE HYBRIDIZATION

A method to isolate unique messenger RNA sequences from paired sources, by subtracting common sequences, for complementary-DNA production.

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Gordon, S. Alternative activation of macrophages. Nat Rev Immunol 3, 23–35 (2003). https://doi.org/10.1038/nri978

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