Gordon S, Taylor PRMonocyte and macrophage heterogeneity. Nat Rev Immunol 5:953-964

Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
Nature reviews. Immunology (Impact Factor: 34.99). 01/2006; 5(12):953-64. DOI: 10.1038/nri1733
Source: PubMed


Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.

    • "With injury, resident microglia or macrophages infiltrating from the circulation become polarized towards a pro-inflammatory (M1) phenotype upon exposure to pro-inflammatory cytokines IFN-γ, TNF-α and cellular or bacterial debris. These cells then produce pro-inflammatory cytokines (TNF-α, interleukin (IL)- 1β, IL-12), present antigen, and express high levels of inducible NO (iNOS) for NO production (Gordon and Taylor, 2005; Villalta et al., 2009). This action is geared to kill the offending foreign pathogen and polarize T-cells to mount an adaptive immune response. "
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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.
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    • "Two distinct states of polarized activation for macrophages have been defined: the classically activated macrophage phenotype, M1, and the alternatively activated macrophage phenotype, M2 (Gordon and Taylor, 2005; Mantovani et al., 2002). M1 macrophages are effector cells in T H 1 cellular immune responses, whereas M2 macrophages appear to promote immune suppression and wound healing/tissue repair (Gordon and Taylor, 2005; Mantovani et al., 2002). Recent evidence demonstrates that in lean animals, higher numbers of macrophages are M2 polarized, possessing anti-inflammatory potential by producing IL-10, while obesity drives pro-inflammatory M1 polarization (Lumeng et al., 2007a,b; Mjosberg et al., 2011). "
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    ABSTRACT: The polarization of tissue resident macrophages toward the alternatively activated, anti-inflammatory M2 phenotype is believed to positively impact obesity and insulin resistance. Here we show that the soluble form of the extracellular domain (ECD) of C-type lectin-like receptor 2, CLEC2, regulates Kupffer cell polarization in the liver and improves glucose and lipid parameters in diabetic animal models. Over-expression of Fc-CLEC2(ECD) in mice via in vivo gene delivery, or injection of recombinant Fc-CLEC2(ECD) protein, results in a reduction of blood glucose and liver triglyceride levels and improves glucose tolerance. Furthermore, Fc-CLEC2(ECD) treatment improves cytokine profiles and increases both the M2 macrophage population and the genes involved in the oxidation of lipid metabolism in the liver. These data reveal a previously unidentified role for CLEC2 as a regulator of macrophage polarity, and establish CLEC2 as a promising therapeutic target for treatment of diabetes and liver disease.
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    • "For this reason, M␾ are highly plastic and signals that they encounter within tissue can alter their activation state, number and function (Mosser and Edwards 2008; Mylonas et al. 2009). Thus both sterile injury and bacterial infection can stimulate them to adopt a 'classical' or 'M1' phenotype that instigates further inflammatory cell recruitment through the production of pro-inflammatory mediators, such as IL-1␤ and TNF (Gordon and Taylor 2005; Mosser and Edwards 2008). In contrast, phagocytosis of apoptotic cells (Voll et al. 1997; McDonald et al. 1999) or exposure to Th2 type cytokines, such as IL-4, IL-13 and IL- 10 can lead to adoption of an 'alternatively-activated' or 'M2' M␾ phenotype. "
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    ABSTRACT: Tissue resident macrophages have vital homeostatic roles in many tissues but their roles are less well defined in the heart. The present study aimed to identify the density, polarisation status and distribution of macrophages in the healthy murine heart and to investigate their ability to respond to immune challenge. Histological analysis of hearts from CSF-1 receptor (csf1-GFP; MacGreen) and CX3CR1 (Cx3cr1(GFP/+)) reporter mice revealed a sparse population of GFP positive macrophages that were evenly distributed throughout the left and right ventricular free walls and septum. F4/80+CD11b+ cardiac macrophages, sorted from myocardial homogenates, were able to phagocytose fluorescent beads in vitro and expressed markers typical of both 'M1' (IL-1β, TNF and CCR2) and 'M2' activation (Ym1, Arg 1, RELMα and IL-10), suggesting no specific polarisation in healthy myocardium. Exposure to Th2 challenge by infection of mice with helminth parasites Schistosoma mansoni, or Heligmosomoides polygyrus, resulted in an increase in cardiac macrophage density, adoption of a stellate morphology and increased expression of Ym1, RELMα and CD206 (mannose receptor), indicative of 'M2' polarisation. This was dependent on recruitment of Ly6ChighCCR2+ monocytes and was accompanied by an increase in collagen content. In conclusion, in the healthy heart resident macrophages are relatively sparse and have a phagocytic role. Following Th2 challenge this population expands due to monocyte recruitment and adopts an 'M2' phenotype associated with increased tissue fibrosis. Copyright © 2015 The Authors. Published by Elsevier GmbH.. All rights reserved.
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