Article

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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    • "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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    • "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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