Trends in Immunology
The chemokine system in diverse forms of macrophage activation and polarization
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.
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Alberto Mantovani has been a member of the Trends in Immunology Editorial Board since 1999.