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  • Review Article
  • Published:

Transcriptional regulation of macrophage polarization: enabling diversity with identity

Nature Reviews Immunology volume 11, pages 750–761 (2011)Cite this article

Subjects

Key Points

  • The macrophage lineage includes a remarkable variety of cells with different functions and functional states that are specified by the complex interplay between microenvironmental signals and a hardwired differentiation programme that determines macrophage identity.

  • The global regulatory landscape of macrophage-specific genes is controlled by the ETS family transcription factor PU.1, which dictates the general context in which sequence-specific transcription factors that are regulated by external stimuli operate to modulate macrophage phenotype and function.

  • Different sequence-specific transcription factors regulate macrophage polarization in specific contexts. Signal transducer and activator of transcription (STAT) proteins are pivotal factors in M1 and M2 macrophage polarization in response to T cell-derived cytokines; peroxisome proliferator-activated receptor-γ regulates the M2-like phenotype of macrophages in adipose tissue; and CCAAT/enhancer-binding protein-β activation mediated by cAMP-responsive element-binding protein drives the induction of M2 macrophages in muscle injury.

  • The polarized phenotype of macrophages is reinforced by the mutual exclusivity of signalling pathways and reciprocal regulation of M1 and M2 genes.

  • Tumour-associated macrophages (TAMs) are a unique polarized macrophage population characterized by the expression of both M1 and M2 marker genes. The specific transcriptional mechanisms that regulate the TAM phenotype remain poorly defined.

Abstract

In terms of both phenotype and function, macrophages have remarkable heterogeneity, which reflects the specialization of tissue-resident macrophages in microenvironments as different as liver, brain and bone. Also, marked changes in the activity and gene expression programmes of macrophages can occur when they come into contact with invading microorganisms or injured tissues. Therefore, the macrophage lineage includes a remarkable diversity of cells with different functions and functional states that are specified by a complex interplay between microenvironmental signals and a hardwired differentiation programme that determines macrophage identity. In this Review, we summarize the current knowledge of transcriptional and chromatin-mediated control of macrophage polarization in physiology and disease.

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Figure 1: The mononuclear phagocyte system.
Figure 2: Transcriptional control of macrophage identity and polarization.
Figure 3: Macrophage polarization in physiology and disease.
Figure 4: Mutual exclusivity and feed-forward signalling maintain macrophage polarization states.
Figure 5: Signal transduction pathways to M1 and M2 macrophage polarization.

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Acknowledgements

T.L. is a research director of the Institut National de la Santé et de la Recherche Médicale (INSERM) supported by grants from the European Research Council (ERC) and the Agence Nationale de la Recherche (ANR), and institutional grants from INSERM, the Centre National de la Recherche Scientifique (CNRS) and the Université de la Méditerranée. Research in this area in the laboratory of G.N. is supported by the ERC.

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  1. Centre d'Immunologie Marseille-Luminy, Parc Scientifique & Technologique de Luminy, Case 906, Marseille, F-13288, France

    Toby Lawrence

  2. Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, Milan, 20139, Italy

    Gioacchino Natoli

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Glossary

Mononuclear phagocyte system

(MPS). A group of bone marrow-derived cells with different morphologies (monocytes, macrophages and dendritic cells), which are mainly responsible for phagocytosis, cytokine secretion and antigen presentation.

M1 macrophages

Macrophages with an activation phenotype associated with increased microbicidal activity and antigen-presenting function. M1-type activation is usually modelled in vitro by interferon-γ and/or lipopolysaccharide stimulation. In mice, M1-associated markers include interleukin-12, MHC class II molecules and nitric oxide synthase 2 (NOS2); however, human macrophages do not show induction of NOS2 in these conditions, despite having a similar functional phenotype.

M2 macrophages

Macrophages that are associated with parasitic infections and T helper 2-type immune responses. M2-type activation is usually modelled in vitro by interleukin-4 (IL-4) and/or IL-13 stimulation. In mice, M2-associated markers include resistin-like-α (also known as FIZZ1), arginase 1, chitinase 3-like 3 (also known as YM1), IL-10 and macrophage mannose receptor 1 (also known as CD206); however, human M2 macrophages do not show induction of resistin-like-α, arginase 1 and chitinase 3-like 3, but instead upregulate indoleamine 2,3-dioxygenase expression. M2 macrophages are associated with anti-inflammatory and homeostatic functions linked to wound healing, fibrosis and tissue repair.

Chromatin immunoprecipitation

(ChIP). A powerful method for assessing the physical association of a known nuclear protein with a candidate target locus in vivo. Cells are first treated with an agent that crosslinks protein to DNA. The chromatin is then sheared into fragments and the protein is immunoprecipitated. If the candidate target region is co-precipitated (as measured by PCR), the target locus is likely to bind the protein (directly or indirectly) in vivo. The immunoprecipitated DNA can also be used for hybridization to high-density microarrays (ChIP–chip) or for high-throughput sequencing (ChIP–seq) to provide a genome-wide view of the binding sites of a specific transcriptional regulator.

Gene promoters

The regulatory regions to which RNA polymerase binds to initiate transcription. Upstream of the RNA polymerase recruitment site (core promoter) is a regulatory promoter where transcription factors bind to control recruitment of the transcriptional machinery.

Enhancers

Control elements located at variable distances from the genes they regulate and to which multiple regulatory proteins bind, thereby influencing gene transcription. In vitro, enhancers function in an orientation- and position-independent manner, but it is not clear whether this is also true in vivo.

Primary response genes

Inducible genes whose transcription does not require new protein synthesis.

Secondary response genes

Inducible genes whose transcription requires new protein synthesis (often the synthesis of transcription factors required for the activation of these genes).

SWI/SNF complex

An ATP-dependent chromatin-remodelling protein complex that was initially identified in yeast. Related complexes exist in mammals and are involved in the remodelling of the chromatin of various genes.

Gamma-activated sequences

DNA binding sites specific for signal transducer and activator of transcription 1 (STAT1) homodimers that mediate the response to interferon-γ.

Interferon-stimulated response elements

(ISREs). Common DNA motifs that are bound by interferon-regulatory factors (IRFs). These elements were initially known as IRF enhancers (IRFEs).

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Lawrence, T., Natoli, G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11, 750–761 (2011). https://doi.org/10.1038/nri3088

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