MACROPHAGE PLASTICITY AND POLARIZATION IN VIVO VERITAS PDF

Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions e. However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies. Introduction Macrophages are an essential component of innate immunity and play a central role in inflammation and host defense 1. Moreover, these cells fulfill homeostatic functions beyond defense, including tissue remodeling in ontogenesis and orchestration of metabolic functions 1 — 3.

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Avogadro, Novara, Italy. Phone: Find articles by Sica, A. Find articles by Mantovani, A. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions e.

However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.

Introduction Macrophages are an essential component of innate immunity and play a central role in inflammation and host defense 1. Moreover, these cells fulfill homeostatic functions beyond defense, including tissue remodeling in ontogenesis and orchestration of metabolic functions 1 — 3. Cells of the monocyte-macrophage lineage are characterized by considerable diversity and plasticity.

In tissues, mononuclear phagocytes respond to environmental cues e. The M1 phenotype is characterized by the expression of high levels of proinflammatory cytokines, high production of reactive nitrogen and oxygen intermediates, promotion of Th1 response, and strong microbicidal and tumoricidal activity.

In contrast, M2 macrophages are considered to be involved in parasite containment and promotion of tissue remodeling and tumor progression and to have immunoregulatory functions.

They are characterized by efficient phagocytic activity, high expression of scavenging molecules, the expression of mannose and galactose receptors, production of ornithine and polyamines through the arginase pathway, and an ILloILhiIL-1decoyRhiIL-1RAhi phenotype 1 , 4. M1-M2 macrophages also are distinct in their chemokine expression profiles.

Signals including IL, glucocorticoid hormones, molecules released from apoptotic cells, and immune complexes also profoundly affect monocyte-macrophage function. These signals induce expression of functional phenotypes that share selected properties with M2 cells e. Operationally, we refer to these cells as M2 like 5. Plasticity and flexibility are key features of mononuclear phagocytes and of their activation states 2 , 4 , 6.

The phenotype of polarized M1-M2 macrophages can, to some extent, be reversed in vitro and in vivo 7 , 8. Moreover, pathology is frequently associated with dynamic changes in macrophage activation, with classically activated M1 cells implicated in initiating and sustaining inflammation and M2 or M2-like cells associated with resolution or smoldering chronic inflammation 9.

It remains unclear whether the mechanism of these switches involves the recruitment of circulating precursors or the reeducation of cells in situ.

However, it is now apparent that specialized or polarized T cells Th1, Th2, Tregs that are key orchestrators of macrophage polarized activation 2 also exhibit previously unsuspected flexibility and plasticity Here, we will focus on recent progress in understanding the molecular basis underlying macrophage polarization, including signaling pathways, transcription factors, and epigenetic regulation.

Moreover, the dynamics and limitations in our understanding of polarized macrophage activation in vivo will be discussed, focusing on selected pathological conditions for references to pathology not discussed here, see Supplemental References; supplemental material available online with this article; doi: Previous reviews also provide a framework for this work 1 — 3 , 6 , Molecular determinants of macrophage polarization A network of signaling molecules, transcription factors, epigenetic mechanisms, and posttranscriptional regulators underlies the different forms of macrophage activation.

The IL-4 type I and type II receptors 1 , 13 activate Stat6, which in turn activates transcription of genes typical of M2 polarization, e. Figure 1 Mechanisms of macrophage polarization. The major pathways of macrophage polarization are outlined. The crosstalk between the M1-M2 macrophage—polarizing pathways is also indicated.

IL-4—induced c-Myc activity controls a subset of M2-associated genes. Epigenetic changes and noncoding RNAs also participate in directing macrophage polarization 32 — IL-4 induces upregulation of the histone demethylase JMJD3 in mouse macrophages, which alters chromatin modifications to promote expression of M2 genes and inhibit M1 genes.

Pathology Resolution of inflammation and repair. Remodeling and repair occur dynamically during ontogenesis and inflammation, and these processes are orchestrated by macrophages. Macrophages undergo dynamic changes during different phases of wound healing. M1-polarized macrophages mediate tissue damage and initiate inflammatory responses 1 , 2.

During the early stages of the repair response after wounding the skin, infiltrating macrophages have an M2 phenotype and their depletion inhibits the formation of a highly vascularized, cellular granulation tissue and of scar tissues In a peritoneal model of inflammation, resolution phase macrophages expressed a unique mixed M1-M2 phenotype, and cAMP was essential to restrain M1 activation In humans, chronic venous ulcers CVU represent a failure to resolve a chronic inflammatory condition Correlative analysis in patients and a mouse model suggested that in CVU the infiltrating macrophages fail to switch from an M1 to an M2 phenotype Notably, iron metabolism is differentially regulated in polarized macrophages It is tempting to speculate that similar mechanisms may underlie M2 functions in patients with severe burns, where hemorrhage and tissue damage, along with the high release of iron by M2 macrophages 42 , may result in high iron tissue levels Dynamic changes in the phenotype of recruited mononuclear phagocytes have been observed in models of ischemic heart disease 44 , suggesting that this is a general feature of the natural history of repair processes.

This observation may suggest a functional link between oxygen deprivation, as occurring in wounds and tumors, and progressive induction of proarteriogenic M2 macrophages. Thus, although the macrophage phenotype in resolution need not be a phenocopy of in vitro—generated M2 cells, preclinical and clinical evidence support the long-held view of a key role of polarized macrophages in tissue repair.

In a model of retinal neuropathy, mononuclear phagocyte infiltration generates a neuroprotective microenvironment promoting retinal progenitor cell survival The interplay of polarized macrophages with stem and progenitor cells is likely a key component of their role in repair and remodeling, although the actual tissue-protective significance of polarized macrophages in degenerative diseases and their involvement with stem and progenitor cells remain to be determined see Supplemental References.

Macrophage activation has been found in autoimmune and inflammatory diseases and in particular in lupus nephritis In a murine model of SLE, proinflammatory activation of macrophages was sustained by Notch signaling Conversely, the acute phase protein serum amyloid P SAP skewed macrophages toward an antiinflammatory M2-like phenotype, thus alleviating lupus nephritis Infection Bacteria.

M1 macrophages are generally considered responsible for resistance against intracellular pathogens and characterize infection with Listeria monocytogenes 55 , Salmonella typhi, and Salmonella typhimurium 56 , as well as the early phases of infection with Mycobacterium tuberculosis 57 , Mycobacterium ulcerans, and Mycobacterium avium 58 , Uncontrolled M1 inflammation associated with acute infections with E.

The M1-M2 switch observed during the transition from acute to chronic infection may provide protection against overwhelming uncontrolled inflammation; however, a phenotype switch can also favor pathogens that have evolved strategies to interfere with M1-associated killing 58 , 61 — Chronic inflammation and granuloma formation are characterized by the presence of macrophages with an epithelial morphology and by macrophage homotypic fusion with the formation of multinucleated giant cells MNG IL-4—mediated upregulation of E-cadherin, which engages in intercellular homotypic adhesion, is likely to underlie MNG formation.

The actual function and role of MNG remain elusive. In experimental and human parasite infections, macrophages generally undergo a dynamic switch toward M2 polarization 61 , The early and late phases of Taenia crassiceps infection are characterized by Th1-driven M1 and Th2-driven IL-4—mediated M2 polarization of macrophages, respectively 11 , A similar M1-M2 switch has been reported during Schistosoma mansoni and Trypanosoma congolense infection In the chronic stage of T.

The recurrent association of M2 polarization with parasite infections does not necessarily imply a generalized relevance in pathogenesis.

Viral infections. Polarized activation of macrophages has been associated with virus infection e. Allergy Allergy is driven by Th2 cells and products and is associated with M2 polarization of macrophages 72 , IL-4—inducible chemokines acting on CCR4 e.

Evidence now indicates that chitin- and arginase-dependent M2 pathways play an active role in pathogenesis 75 , Asthma is associated with tissue remodeling, including collagen deposition and goblet cell hyperplasia. IL-4—driven M2 polarization is likely to play a key role as an orchestrator of these processes Moreover, a Th1-associated cytokine, IL, has also been implicated in allergic inflammation It is therefore perhaps not surprising that mixed phenotype macrophages have been observed Cancer Cancer-related inflammation is characterized by the recruitment of cells of the monocyte-macrophage lineage to tumor tissues 2 , 82 , 83 , which also condition the premetastatic niche, to favor secondary localization of cancer.

Classically activated M1-polarized macrophages have the potential to exhibit antitumor activity and to elicit tumor tissue disruption 4. At least in some models of carcinogenesis in the mouse, progression is associated with a phenotype switch from M1 to M2 Th1-driven macrophage activation was found to mediate elimination of senescent hepatocytes, which drive subsequent carcinogenesis It is therefore likely that classically activated M1 macrophages contribute to the T cell—mediated elimination and equilibrium phases during tumor progression At later stages of progression in mice and humans, TAMs generally have an M2-like phenotype with low IL expression, high IL expression, and low tumoricidal activity and promotion of tissue remodeling and angiogenesis.

TAM infiltration is generally associated with poor prognosis, as shown in Hodgkin disease, glioma, cholangiocarcinoma, and breast carcinoma 87 , However, TAMs with various functional states can coexist in the same tumor 2 , Various pathways orchestrate the protumor function of myelomonocytic cells, including tumor-derived and host-derived signals 2. Lymphocytes are key orchestrators of TAM function 2 , but pathways differ in tumors originating in different organs.

For instance, skewing of macrophage function was found to be mediated by IL-4—producing Th2 cells in skin 90 , 91 and by antibody-producing B cells in breast carcinogenesis 92 , B1 cells can promote cancer progression in the skin 5 , and fibroblasts can also contribute to circuits driving macrophage polarization and tumor promotion The identification of the various cellular and molecular pathways that participate in inflammation in different human cancers will be required to translate our understanding of cancer-related inflammation to meaningful therapeutic advances.

Obesity and metabolism Obesity-associated insulin resistance, diabetes, and metabolic syndrome are sustained by chronic subclinical inflammation Adipose tissue macrophages ATMs are a major component of adipose tissue and are important players in obesity-associated pathology. In turn, ATM-produced inflammatory cytokines e.

ATM infiltration correlates with the degree of obesity — ATM accumulation is orchestrated by selected chemokines and their receptors e. Weight loss is associated with a shift back to an M2-like phenotype. Progress has been made in defining the molecular pathways that account for polarization of ATMs 19 , 20 , 24 , , in obesity.

The adipose tissue of obese subjects shows a marked reduction in KLF4 levels. Nguyen et al. Although further work is needed to dissect the diversity and dynamics of ATMs, M2-like cells in nonobese individuals are likely involved in maintaining adipose tissue homeostasis, preventing inflammation, and promoting insulin sensitivity.

In contrast, M1-like ATMs drive obesity-associated inflammation and insulin resistance The role of macrophages in obesity and associated disorders underlines a homeostatic function of macrophages in metabolism as cells capable of reorienting their own metabolic activity and as orchestrators of general metabolism.

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Macrophage plasticity and polarization: In vivo veritas

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