Chapter Six - Macrophage Activation and Polarization as an Adaptive Component of Innate Immunity

https://doi.org/10.1016/B978-0-12-417028-5.00006-5Get rights and content

Abstract

Innate immunity has an adaptive component, which has been referred to as “memory,” “trained,” “imprinted” or “adaptive.” Plasticity is a hallmark of cells of the monocyte–macrophage lineage. Microbial recognition and cytokines profoundly affect macrophage function causing a range of adaptive responses including activation, priming, or tolerance. These adaptive responses of macrophages include production of humoral fluid-phase pattern recognition molecules such as the prototypic long pentraxin PTX3. These components of humoral innate immunity in turn cooperate with and regulate phagocyte function. Progress has been made in defining the molecular basis underlying the polarized activation of macrophages, including signaling mediators, transcription factors, epigenetic modifications, and the microRNA network. The definition of molecules and mechanisms associated with plasticity and polarized activation of macrophages may provide a basis for innovative diagnostic and therapeutic approaches.

Introduction

Innate immunity is classically viewed as a first line of resistance against pathogens. More recently, innate immunity receptors have emerged as sensors of tissue damage and metabolic dysfunction (Medzhitov, 2008, Verbist et al., 2012). Moreover, cells of the innate immune system (macrophages and neutrophils) activate, orient, and regulate adaptive responses.

The innate immune system includes a cellular and a humoral arm. In addition to acting as innate effectors, macrophages and neutrophils are a major source of humoral, fluid-phase pattern recognition molecules (Bottazzi, Doni, Garlanda, & Mantovani, 2010). These include the long pentraxin PTX3, members of the ficolin and collectin family, and serum amyloid A. The production of these functional ancestors of antibodies by phagocytes links the cellular and the humoral arm of innate immunity (Bottazzi et al., 2010).

Macrophages are probably the most plastic cells among cells of hematopoietic origin (Biswas and Mantovani, 2012, Deban et al., 2010, Gordon and Martinez, 2010, Mantovani et al., 2004, Mantovani et al., 2002, Martinez et al., 2009, Mosser and Edwards, 2008, Pollard, 2009, Sica and Mantovani, 2012). In tissues, macrophages acquire unique and distinct morphological and functional properties (e.g., Kupffer cells in the liver and alveolar macrophages in lungs). Moreover, immunological and microbial signals have long been known to “activate” macrophages. Macrophage activation has for a long time been considered essentially a stereotyped transient increase in effector function (antimicrobial and antitumor activity) (Adams and Hamilton, 1984, Mackaness, 1969). The discovery of an alternative form of macrophage activation by IL-4 (Stein, Keshav, Harris, & Gordon, 1992) has opened a new perspective on the diversity of macrophage activation. In response to TLR, ligands and IFN-γ or IL-4/IL-13 macrophages undergo M1 (classical) or M2 (alternative) activation, which mirror the TH1–TH2 polarization and represent extremes of a continuum in a universe of activation states (Biswas and Mantovani, 2010, Mantovani et al., 2002, Mills et al., 2000, Mosser and Edwards, 2008, Sica and Bronte, 2007, Sica and Mantovani, 2012).

In addition to a transient wave of “activation,” microbial encounters and immunological signals shape the innate immune system and condition subsequent responses for days to months (Netea, Quintin, & van der Meer, 2011). The sharp distinction between innate and adaptive immunity is an oversimplification. Early (e.g., Kurtz, 2005, Kurtz and Franz, 2003) and more recent evidence (e.g., Kleinnijenhuis et al., 2012) indicates that microbial encounters shape the “innate” response of phagocytes independently of lymphocytes. Indeed, studies in lower organisms have provided strong unequivocal evidence for an adaptive component in phagocyte responses. This lymphocyte-independent shaping of innate immunity has been referred to as “memory” (Kleinnijenhuis et al., 2012, Kurtz, 2005, Kurtz and Franz, 2003), “adaptive” (Biswas and Mantovani, 2010, Bowdish et al., 2007), or “trained” (Kleinnijenhuis et al., 2012, Netea et al., 2011). Evidence suggests that epigenetic changes occurring during macrophage activation underlie the long-term imprinting of macrophage responses (adaptive innate immunity) by microbial encounters (Chen et al., 2012, Kleinnijenhuis et al., 2012, Lawrence and Natoli, 2011). Here, we will review selected aspects of activation and adaptive responses of macrophages including their importance as a source of fluid-phase pattern recognition molecules, as well as genetic and epigenetic mechanisms underlying macrophage activation and polarization.

Section snippets

Activation, Priming, and Tolerance as Adaptive Responses of Macrophages (Fig. 6.1)

It has long been known that in response to microbial components and cytokines, cells of the monocyte–macrophage lineage exhibit enhanced effector functions including microbicidal and tumoricidal activity (Adams and Hamilton, 1984, Mackaness, 1969; Fig. 6.1). Transcriptional profiling has added a deeper insight into the acquisition of enhanced effector function (e.g., Martinez, Gordon, Locati, & Mantovani, 2006). The wave of classical activation of mononuclear phagocyte is transient. In

Polarized Activation

The identification of an alternative (M2) form of macrophage activation by IL-4 (Stein et al., 1992) opened new vistas on the plasticity of mononuclear phagocytes. Classically and alternatively activated macrophages have been referred to as M1 and M2, mirroring Th1 and Th2 T cells characterized by differential production of the macrophage activation signals IFN-γ and IL-4. Classically activated (M1) macrophages had long been known to be induced by IFN-γ alone or in concert with microbial

Molecular Mechanisms Underlying Macrophage Polarization

Macrophage polarization is tuned by a network of signaling molecules, transcription factors, epigenetic mechanisms, and posttranscriptional regulators. Recent studies have identified key transcriptional events controlling macrophage polarization. M1-promoting signals, interferons and TLR signaling, activate the canonical IRF-STAT signaling pathways (via STAT1), whereas IL-4 and IL-13 skew macrophages toward the M2 phenotype (via STAT6) (Sica & Bronte, 2007). A key regulator of M1 polarization

Epigenetic Regulation of Macrophage Polarization

Epigenetic changes define modifications of histones, or other chromatin proteins, controlling the tissue and context specific expression of information encoded in DNA. These events comprise posttranscriptional modifications, such as methylation, acetylation, and phosphorylation, which together set the “histone code,” to control interaction and functions of selected transcription factors (Ivashkiv, 2013). New evidence indicates that different chromatin states of relevant gene loci control

Posttanscriptional Regulation in Macrophage Activation and Polarization

MicroRNA (miRs) are small noncoding RNA molecules that control gene expression targeting mRNA 3′UTRs (Bartel, 2009). As a large number of miRNA have been identified and each single miRNA targets and controls several mRNA transcripts, this posttranscriptional mechanism is emerging as a major player in the control of several biological processes. Evidence indicates their involvement also in the regulation of the gene expression profile, characterizing distinct macrophage polarities. In

Concluding Remarks

Plasticity and flexibility are key features of mononuclear phagocytes and of their activation states. Individual tissue microenvironments shape the phenotype and function of cells of the monocyte–macrophage lineage. The integration of tissue-specific cues, microbial encounters, and cytokines dictates differentiation and activation of these cells.

Specific targeting of macrophages, their subsets, or activation states remains a holy grail for therapeutic intervention. Drugs not specifically

Acknowledgments

Alberto Mantovani is supported by AIRC (Investigator Grant and 5x1000 Grant) and the European Commission (FP7-HEALTH-2011-ADITEC-280873).

References (126)

  • S. Gordon et al.

    Alternative activation of macrophages: Mechanism and functions

    Immunity

    (2010)
  • J.W. Graff et al.

    Identifying functional microRNAs in macrophages with polarized phenotypes

    Journal of Biological Chemistry

    (2012)
  • L.B. Ivashkiv

    Epigenetic regulation of macrophage polarization and function

    Trends in Immunology

    (2013)
  • M.K. Jang et al.

    The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription

    Molecular Cell

    (2005)
  • P. Jeannin et al.

    Complexity and complementarity of outer membrane protein A recognition by cellular and humoral innate immunity receptors

    Immunity

    (2005)
  • K. Kang et al.

    Adipocyte-derived Th2 cytokines and myeloid PPARdelta regulate macrophage polarization and insulin sensitivity

    Cell Metabolism

    (2008)
  • J. Kurtz

    Specific memory within innate immune systems

    Trends in Immunology

    (2005)
  • G.H. Mahabeleshwar et al.

    The myeloid transcription factor KLF2 regulates the host response to polymicrobial infection and endotoxic shock

    Immunity

    (2011)
  • A. Mantovani et al.

    The chemokine system in diverse forms of macrophage activation and polarization

    Trends in Immunology

    (2004)
  • A. Mantovani et al.

    Macrophage polarization: Tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes

    Trends in Immunology

    (2002)
  • T. Naessens et al.

    Innate imprinting of murine resident alveolar macrophages by allergic bronchial inflammation causes a switch from hypoinflammatory to hyperinflammatory reactivity

    American Journal of Pathology

    (2012)
  • M.A. Nahid et al.

    miR-146a is critical for endotoxin-induced tolerance: Implication in innate immunity

    Journal of Biological Chemistry

    (2009)
  • M.G. Netea et al.

    Trained immunity: A memory for innate host defense

    Cell Host & Microbe

    (2011)
  • W. Noel et al.

    Alternatively activated macrophages during parasite infections

    Trends in Parasitology

    (2004)
  • J.I. Odegaard et al.

    Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance

    Cell Metabolism

    (2008)
  • O.M. Pello et al.

    Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology

    Blood

    (2012)
  • F. Rae et al.

    Characterisation and trophic functions of murine embryonic macrophages based upon the use of a Csf1r-EGFP transgene reporter

    Developmental Biology

    (2007)
  • H. Roca et al.

    CCL2 and interleukin-6 promote survival of human CD11b + peripheral blood mononuclear cells and induce M2-type macrophage polarization

    Journal of Biological Chemistry

    (2009)
  • D. Ruckerl et al.

    Induction of IL-4Ralpha-dependent microRNAs identifies PI3K/Akt signaling as essential for IL-4-driven murine macrophage proliferation in vivo

    Blood

    (2012)
  • D.O. Adams et al.

    The cell biology of macrophage activation

    Annual Review of Immunology

    (1984)
  • F.A. Amaral et al.

    Commensal microbiota is fundamental for the development of inflammatory pain

    Proceedings of the National Academy of Sciences of the United States of America

    (2008)
  • C. Auffray et al.

    Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior

    Science

    (2007)
  • S.K. Biswas et al.

    Macrophage plasticity and interaction with lymphocyte subsets: Cancer as a paradigm

    Nature Immunology

    (2010)
  • B. Bottazzi et al.

    An integrated view of humoral innate immunity: Pentraxins as a paradigm

    Annual Review of Immunology

    (2010)
  • A.A. Chaudhuri et al.

    MicroRNA-125b potentiates macrophage activation

    Journal of Immunology

    (2011)
  • X. Chen et al.

    Requirement for the histone deacetylase Hdac3 for the inflammatory gene expression program in macrophages

    Proceedings of the National Academy of Sciences of the United States of America

    (2012)
  • J. Chen et al.

    IFN-gamma abrogates endotoxin tolerance by facilitating Toll-like receptor-induced chromatin remodeling

    Proceedings of the National Academy of Sciences of the United States of America

    (2010)
  • G. Curtale et al.

    Negative regulation of toll-like receptor 4 signaling by the IL-10 dependent microRNA-146b

    Proceedings of the National Academy of Sciences of the United States of America

    (2013)
  • F. De Santa et al.

    Jmjd3 contributes to the control of gene expression in LPS-activated macrophages

    EMBO Journal

    (2009)
  • L. Deban et al.

    Regulation of leukocyte recruitment by the long pentraxin PTX3

    Nature Immunology

    (2010)
  • A. Didierlaurent et al.

    The impact of successive infections on the lung microenvironment

    Immunology

    (2007)
  • A. Didierlaurent et al.

    Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection

    The Journal of Experimental Medicine

    (2008)
  • C.A. Dinarello

    Blocking IL-1 in systemic inflammation

    The Journal of Experimental Medicine

    (2005)
  • C.K. Glass et al.

    Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells

    Nature Reviews. Immunology

    (2010)
  • C.A. Gleissner et al.

    CXC chemokine ligand 4 induces a unique transcriptome in monocyte-derived macrophages

    Journal of Immunology

    (2010)
  • S. Gordon

    Alternative activation of macrophages

    Nature Reviews. Immunology

    (2003)
  • C. Gustafsson et al.

    Gene expression profiling of human decidual macrophages: Evidence for immunosuppressive phenotype

    PLoS One

    (2008)
  • T. Hagemann et al.

    “Re-educating” tumor-associated macrophages by targeting NF-kappaB

    The Journal of Experimental Medicine

    (2008)
  • M.S. Han et al.

    JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation

    Science

    (2013)
  • R.N. Hanna et al.

    NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and increases atherosclerosis

    Circulation Research

    (2012)
  • Cited by (0)

    View full text