Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.

/pdf/exploring-the-full-spectrum-of-macrophage-activation-b5rnrcgcen.pdf

Exploring the full spectrum of macrophage activation.

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

/pdf/microenvironmental-regulation-of-tumor-progression-and-4528oymlw6.pdf

Microenvironmental regulation of tumor progression and metastasis.

Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. 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.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). 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.

/pdf/macrophage-plasticity-and-polarization-in-vivo-veritas-3j0n8qsu6m.pdf

Macrophage plasticity and polarization: in vivo veritas

https://www.cell.com/immunity/pdf/S1074-7613(14)00228-3.pdf

Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines

Macrophages are strategically located throughout the body tissues, where they ingest and process foreign materials, dead cells and debris and recruit additional macrophages in response to inflammatory signals They are highly heterogeneous cells that can rapidly change their function in response to local microenvironmental signals In this Review, we discuss the four stages of orderly inflammation mediated by macrophages: recruitment to tissues; differentiation and activation in situ; conversion to suppressive cells; and restoration of tissue homeostasis We also discuss the protective and pathogenic functions of the various macrophage subsets in antimicrobial defence, antitumour immune responses, metabolism and obesity, allergy and asthma, tumorigenesis, autoimmunity, atherosclerosis, fibrosis and wound healing Finally, we briefly discuss the characterization of macrophage heterogeneity in humans

/pdf/protective-and-pathogenic-functions-of-macrophage-subsets-5d5nlezyqd.pdf

Protective and pathogenic functions of macrophage subsets

Nature Reviews Immunology 8, 958–969 (2008) The authors would like to include as an addendum the contribution of R. Stout and J. Suttles to the conceptual framework of macrophage plasticity that was mentioned in our Review. Their ideas on the ability of macrophages to change their functional phenotype in response to their tissue environment were previously published in two review articles (J.

Erratum: Exploring the full spectrum of macrophage activation

We generated three populations of macrophages (Mphi) in vitro and characterized each. Classically activated Mphi (Ca-Mphi) were primed with IFN-gamma and stimulated with LPS. Type II-activated Mphi (Mphi-II) were similarly primed but stimulated with LPS plus immune complexes. Alternatively activated Mphi (AA-Mphi) were primed overnight with IL-4. Here, we present a side-by-side comparison of the three cell types. We focus primarily on differences between Mphi-II and AA-Mphi, as both have been classified as M2 Mphi, distinct from Ca-Mphi. We show that Mphi-II more closely resemble Ca-Mphi than they are to AA-Mphi. Mphi-II and Ca-Mphi, but not AA-Mphi, produce high levels of NO and have low arginase activity. AA-Mphi express FIZZ1, whereas neither Mphi-II nor Ca-Mphi do. Mphi-II and Ca-Mphi express relatively high levels of CD86, whereas AA-Mphi are virtually devoid of this costimulatory molecule. Ca-Mphi and Mphi-II are efficient APC, whereas AA-Mphi fail to stimulate efficient T cell proliferation. The differences between Ca-Mphi and Mphi-II are more subtle. Ca-Mphi produce IL-12 and give rise to Th1 cells, whereas Mphi-II produce high levels of IL-10 and thus, give rise to Th2 cells secreting IL-4 and IL-10. Mphi-II express two markers that may be used to identify them in tissue. These are sphingosine kinase-1 and LIGHT (TNF superfamily 14). Thus, Ca-Mphi, Mphi-II, and AA-Mphi represent three populations of cells with different biological functions.

https://jlb.onlinelibrary.wiley.com/doi/epdf/10.1189/jlb.0406249

Biochemical and functional characterization of three activated macrophage populations

NF-κB1 (p50) Homodimers Differentially Regulate Pro- and Anti-inflammatory Cytokines in Macrophages *

To gain insight into the molecular mechanism(s) whereby macrophages produce large amounts of IL-10, we analyzed IL-10 gene expression and temporally correlated it with modifications to chromatin associated with the IL-10 promoter. In resting cells, which make essentially no cytokines, the IL-10 promoter is associated with histones containing little or no detectable modifications. Macrophages stimulated in the presence of immune complexes begin to produce high levels of IL-10 pre-mRNA transcripts within minutes of stimulation. Coincident with this transcription was a rapid and dynamic phosphorylation of histone H3 at specific sites in the IL-10 promoter. Histone phosphorylation was closely followed by the binding of transcription factors to the IL-10 promoter. Blocking the activation of ERK prevented histone phosphorylation and transcription factor binding to the IL-10 promoter. In contrast to histone phosphorylation, the peak of histone acetylation at this promoter did not occur until after transcription had peaked. Inhibition of histone deactylase did not alter IL-10 gene expression, suggesting that phosphorylation but not acetylation was the proximal event responsible for IL-10 transcription. Our findings reveal a rapid and well-orchestrated series of events in which ERK activation causes a rapid and transient phosphorylation of histone H3 at specific regions of the IL-10 promoter, resulting in a transient exposure of the IL-10 promoter to the transcription factors that bind there. This exposure is essential for the efficient induction of IL-10 gene expression in macrophages. To our knowledge, this represents a unique way in which the expression of a cytokine gene is regulated in macrophages.

/pdf/dynamic-and-transient-remodeling-of-the-macrophage-il-10-zdc1lnh830.pdf

Justin P. Edwards

Papers

Exploring the full spectrum of macrophage activation.

Erratum: Exploring the full spectrum of macrophage activation

Biochemical and functional characterization of three activated macrophage populations

NF-κB1 (p50) Homodimers Differentially Regulate Pro- and Anti-inflammatory Cytokines in Macrophages *

Dynamic and Transient Remodeling of the Macrophage IL-10 Promoter during Transcription