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