Alternative Activation of Macrophages: An Immunologic Functional Perspective

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom.
Annual Review of Immunology (Impact Factor: 41.39). 04/2009; 27(1):451-83. DOI: 10.1146/annurev.immunol.021908.132532
Source: PubMed

ABSTRACT Macrophages are innate immune cells with well-established roles in the primary response to pathogens, but also in tissue homeostasis, coordination of the adaptive immune response, inflammation, resolution, and repair. These cells recognize danger signals through receptors capable of inducing specialized activation programs. The classically known macrophage activation is induced by IFN-gamma, which triggers a harsh proinflammatory response that is required to kill intracellular pathogens. Macrophages also undergo alternative activation by IL-4 and IL-13, which trigger a different phenotype that is important for the immune response to parasites. Here we review the cellular sources of these cytokines, receptor signaling pathways, and induced markers and gene signatures. We draw attention to discrepancies found between mouse and human models of alternative activation. The evidence for in vivo alternative activation of macrophages is also analyzed, with nematode infection as prototypic disease. Finally, we revisit the concept of macrophage activation in the context of the immune response.

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    • "IR insulin receptor, TNFα tumour necrosis factor α, TNFR TNFα receptor, SFAs saturated fatty acids, Tlr2/4 toll-like receptors 2/4, CD36/FAT cluster of differentiation-36/fatty acid translocase, IL-1β interleukin-1β, IL1-R interleukin-1 receptor, IL-4 interleukin-4, IL-13 interleukin-13, IL-4R IL-4 receptor, IL-13R IL-13 receptor, JAK3 Janus-associated kinase N. Dali-Youcef and R. Ricci the alternative activation of macrophages. The T H2 cytokines IL-4 and IL-13, which stimulate M2-type macrophage conversion, induce Janus-associated kinase (JAK) activity that phosphorylates STAT6, resulting in its nuclear translocation and STAT6-mediated transcription (Martinez et al. 2009). STAT6, PPARγ and PPARγ coactivator 1β (PGC-1β) cooperatively act to engage oxidative metabolism by enhancing fatty acid oxidation and mitochondrial biogenesis. "
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    Handbook of experimental pharmacology 04/2015; DOI:10.1007/164_2015_4
    • "IL-10, IL-13, TGF-β), VEGF, EGF, Arg1) to deactivate pro-inflammatory cell phenotypes and re-establish homeostasis (Gordon, 2003; Gordon and Martinez, 2010; Ortega-Gómez et al., 2013). This includes production of IL-10 to down-regulate inflammatory cells, extracellular matrix protecting proteins like Ym1/2, ornithine , polyamines for wound repair and higher levels of receptors associated with phagocytosis (Martinez et al., 2009). IL-10 induces STAT3 and downstream genes including Il10, Tgfb1, macrophage mannose receptor Mrc1 (Lang et al., 2002; Gordon, 2003). "
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    ABSTRACT: Microglia are critical nervous system-specific immune cells serving as tissue resident macrophages influencing brain development, maintenance of the neural environment, response to injury, and repair. As influenced by their environment, microglia assume a diversity of phenotypes and retain the capability to shift functions to maintain tissue homeostasis. In comparison to peripheral macrophages, microglia demonstrate similar and unique features with regards to phenotype polarization, allowing for innate immunological functions. Microglia can be stimulated by lipopolysaccharide or interferon gamma to a M1 phenotype for expression of pro-inflammatory cytokines or by IL4/IL13 to a M2 phenotype for resolution of inflammation and tissue repair. Increasing evidence suggests a role of metabolic reprogramming in the regulation of the innate inflammatory response. Studies using peripheral immune cells demonstrate that polarization to an M1 phenotype is often accompanied by a shift in cells from oxidative phosphorylation to aerobic glycolysis for energy production. More recently, the link between polarization and mitochondrial energy metabolism has been considered in microglia. Under these conditions, energy demands would be associated with functional activities and cell survival and thus, may serve to influence the contribution of microglia activation to various neurodegenerative conditions. This review examines the polarization states of microglia and the relationship to mitochondrial metabolism. Additional supporting experimental data is provided to demonstrate mitochondrial metabolic shifts in primary microglia and the BV-2 microglia cell line induced under LPS (M1) and IL-4/IL13 (M2) polarization. This article is protected by copyright. All rights reserved.
    British Journal of Pharmacology 03/2015; DOI:10.1111/bph.13139 · 4.99 Impact Factor
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    • "Furthermore, they have strongly enriched Integrin complexes (including Integrins alpha-5, alpha 6, beta-1, beta-2 and beta-5) and express higher levels of Lectins such as mannose receptor 1 (MRC1), Galectins 1, 3, 8 and 9 as well as Chitinase-like protein 3 (Chil3/Ym1) and Sialoadhesin (Siglec1). Interestingly, BMDMs express 205 also 4-times more Clec10a (Mgl1) which has been used with MRC1 and Ym1 as markers for alternatively activated macrophages [26]. RAW 264.7, on the other hand, express higher levels of Clec4e (Mincle), Clec4a (Dcir) and Clec7a (Dectin 1), as well as a 4-fold higher amount of interferon-γ receptor, suggesting that the basal activation state of RAW 264.7 cells is considerably more pro-inflammatory compared to BMDMs. "
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    ABSTRACT: Macrophages are important immune cells operating at the forefront of innate immunity by taking up foreign particles and microbes through phagocytosis. The RAW 264.7 cell line is commonly used for experiments in the macrophage and phagocytosis field. However, little is known how its functions compare to primary macrophages. Here, we have performed an in-depth proteomics characterisation of phagosomes from RAW 264.7 and bone marrow-derived macrophages by quantifying more than 2500 phagosomal proteins. Our data indicates that there are significant differences for a large number of proteins including important receptors such as mannose receptor 1 and Siglec-1. Moreover, BMDM phagosomes mature considerably faster by fusion with endosomes and the lysosome when validated using fluorogenic phagocytic assays. We provide a valuable resource for researcher in the field and recommend careful use of the RAW 264.7 cell line when studying phagosome functions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    PROTEOMICS 02/2015; DOI:10.1002/pmic.201400431 · 3.97 Impact Factor
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