Trends in Immunology
Volume 25, Issue 12, December 2004, Pages 677-686
Journal home page for Trends in Immunology

The chemokine system in diverse forms of macrophage activation and polarization

https://doi.org/10.1016/j.it.2004.09.015Get rights and content

Plasticity and functional polarization are hallmarks of the mononuclear phagocyte system. Here we review emerging key properties of different forms of macrophage activation and polarization (M1, M2a, M2b, M2c), which represent extremes of a continuum. In particular, recent evidence suggests that differential modulation of the chemokine system integrates polarized macrophages in pathways of resistance to, or promotion of, microbial pathogens and tumors, or immunoregulation, tissue repair and remodeling.

Section snippets

Confusing nomenclature of polarized mononuclear phagocytes: a proposal

Interferon-γ (IFN-γ), alone or in concert with microbial products [e.g. lipopolysaccharide (LPS)] or cytokines [e.g. tumor necrosis factor (TNF)], activates macrophages [7]. Classical macrophage activation is characterized by: high capacity to present antigen; high interleukin-12 (IL-12) and IL-23 production [8] and consequent activation of a polarized type I response; and high production of toxic intermediates [nitric oxide (NO), reactive oxygen intermediates (ROI)]. Many have referred to

Functional properties of polarized mononuclear phagocytes

Figure 1, Figure 2 summarize selected properties of polarized macrophage populations. These properties are similar for mouse and human cells, unless specified. Polarized macrophages differ in terms of receptor expression, cytokine production, effector function and, as discussed later, chemokine repertoires. M1 macrophages exposed to the classic activation signals IFN-γ and LPS express opsonic receptors [e.g. FcγRIII (CD16)], whereas M2 macrophages are characterized by abundant levels of

Chemokine receptor repertoire during monocyte–macrophage differentiation

Circulating monocytes are heterogeneous in several respects and recent evidence indicates that the chemokine receptors CX3CR1 and CCR2 are differentially expressed in mouse mononuclear phagocytes [19]. A first subset, mostly overlapping with the CD16+ subpopulation, is characterized by high CX3CR1 expression and low levels of inflammatory chemokine receptors (CCR1 and CCR2), as well as L-selectin. These cells, indicated as ‘resident monocytes’, preferentially home to non-inflamed tissues, where

Chemokine repertoires during macrophage activation and polarization

Distinct chemokine repertoires associate with M1 and the various forms of M2 macrophage activation. LPS activation of monocytes or macrophages results in the NF-κB-dependent transcription of inflammatory chemokines, such as CXCL1, 2, 3, 5, 8, 9 and 10 and CCL2, 3, 4, 5, 11, 17 and 22 [27]. In addition, LPS and IFN-γ induce the expression of CXCL10, CXCL9 and CCL5 28, 29, 30. LPS mediates induction of the CXCL10, CXCL9 and CCL5 genes through the activation of the transcription factor IFN

Chemokine receptor repertoires during macrophage activation and polarization

The chemokine system is regulated at the level of agonist production and receptor expression [2]. Human monocytes exposed to bacterial LPS show a dramatic downregulation of the CCL2 receptor, CCR2 [62]. This effect is associated with destabilization of the transcript and is not dependent on induction of the agonist. Subsequent work has extended this observation to other proinflammatory signals, including TNF, IL-1 and IFN-γ, as well as to other cell types, such as DCs and activated T and NK

Concluding remarks

Plasticity is a hallmark of the mononuclear phagocyte system. Fully polarized M1 and M2 cells in their various versions are extremes of a continuum. M1 cells might indeed be more diverse than so far realized. Moreover, differentiation might combine with polarizing signals to yield more diverse phenotypes, as illustrated by immature myeloid suppressor cells [68]. With this caveat, polarization of macrophage function is an operationally useful conceptual framework, which crystallizes a continuum

Acknowledgements

This work was supported by the Italian Association for Cancer Research, MIUR (FIRB, COFIN and CNR funding), Fondo Interno per la Ricerca Scientifica e Tecnologica (FIRST), Ministero della Salute and European Commission.

References (69)

  • S. Akira

    Toll-like receptor signaling

    J. Biol. Chem.

    (2003)
  • S. Ito

    Interleukin-10 inhibits expression of both interferon α- and interferon γ-induced genes by suppressing tyrosine phosphorylation of STAT1

    Blood

    (1999)
  • J.K. Riley

    Interleukin-10 receptor signaling through the JAK–STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action

    J. Biol. Chem.

    (1999)
  • D.R. Herbert

    Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology

    Immunity

    (2004)
  • R. Bonecchi

    Divergent effects of IL-4 and interferon γ on macrophage-derived chemokine (MDC) production: an amplification circuit of polarized T helper 2 responses

    Blood

    (1998)
  • E. Galliera

    β-arrestin-dependent constitutive internalization of the human chemokine decoy receptor D6

    J. Biol. Chem.

    (2004)
  • O. Politz

    Pseudoexons and regulatory elements in the genomic sequence of the beta-chemokine, alternative macrophage activation-associated CC-chemokine (AMAC)-1

    Cytokine

    (2000)
  • J.A. Hedrick

    Characterization of a novel CC chemokine, HCC-4, whose expression is increased by interleukin-10

    Blood

    (1998)
  • E. Schutyser

    Identification of biologically active chemokine isoforms from ascitic fluid and elevated levels of CCL18/pulmonary and activation-regulated chemokine in ovarian carcinoma

    J. Biol. Chem.

    (2002)
  • A. Mantovani

    Decoy receptors: a strategy to regulate inflammatory cytokines and chemokines

    Trends Immunol.

    (2001)
  • S. Gordon

    Alternative activation of macrophages

    Nat. Rev. Immunol.

    (2003)
  • D.M. Mosser

    The many faces of macrophage activation

    J. Leukoc. Biol.

    (2003)
  • T.A. Hamilton

    Molecular basis of macrophage activation: from gene expression to phenotypic diversity

  • F.A. Verreck

    Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • M. Stein

    Interleukin 4 potently enhances murine mannose receptor activity: a marker of alternative immunologic macrophage activation

    J. Exp. Med.

    (1992)
  • R. Lang

    Shaping gene expression in activated and resting primary macrophages by IL-10

    J. Immunol.

    (2002)
  • M. Jung

    Expression profiling of IL-10-regulated genes in human monocytes and peripheral blood mononuclear cells from psoriatic patients during IL-10 therapy

    Eur. J. Immunol.

    (2004)
  • M. Locati

    Analysis of the gene expression profile activated by the CC chemokine ligand 5/RANTES and by lipopolysaccharide in human monocytes

    J. Immunol.

    (2002)
  • P. Perrier

    Distinct transcriptional programs activated by interleukin-10 with or without lipopolysaccharide in dendritic cells: induction of the B cell-activating chemokine, CXC chemokine ligand 13

    J. Immunol.

    (2004)
  • Scotton, C. et al. Transcriptional profiling reveals complex regulation of the monocyte IL-1b system by IL-13. J....
  • I. Kurth

    Monocyte selectivity and tissue localization suggests a role for breast and kidney-expressed chemokine (BRAK) in macrophage development

    J. Exp. Med.

    (2001)
  • A. Kaufmann

    Increase of CCR1 and CCR5 expression and enhanced functional response to MIP-1α during differentiation of human monocytes to macrophages

    J. Leukoc. Biol.

    (2001)
  • L. Turner

    Hypoxia inhibits macrophage migration

    Eur. J. Immunol.

    (1999)
  • M.J. Grimshaw

    Inhibition of monocyte and macrophage chemotaxis by hypoxia and inflammation – a potential mechanism

    Eur. J. Immunol.

    (2001)
  • Cited by (4940)

    • Synthesis of urolithin derivatives and their anti-inflammatory activity

      2024, Biochemical and Biophysical Research Communications
    • Macrophage senescence in health and diseases

      2024, Acta Pharmaceutica Sinica B
    View all citing articles on Scopus
    *

    Alberto Mantovani has been a member of the Trends in Immunology Editorial Board since 1999.

    View full text