Adipose tissue macrophages

Adipose tissue macrophages (abbr. ATMs) comprise tissue resident macrophages present in adipose tissue. Adipose tissue apart from adipocytes is composed of the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and variety of immune cells. The latter ones are composed of mast cells, eosinophils, B cells, T cells and macrophages. The number of macrophages within adipose tissue differs depending on the metabolic status. As discovered by Rudolph Leibel and Anthony Ferrante et al. in 2003 at Columbia University, the percentage of macrophages within adipose tissue ranges from 10% in lean mice and humans up to 50% in extremely obese, leptin deficient mice and almost 40% in obese humans. Increased number of adipose tissue macrophages correlates with increased adipose tissue production of proinflammatory molecules and might therefore contribute to the pathophysiological consequences of obesity (e.g. insulin resistance, type 2 diabetes).

Macrophages are remarkably plastic cells which in order to adapt to different tissue microenvironments can assume a range of different phenotypes. Accordingly, macrophages can exhibit either pro- or anti-inflammatory phenotypes and are routinely classified into M1 (classically activated) phenotype and M2 (alternatively activated) phenotype. According to this classification, macrophages acquire M1 phenotype following in vitro stimulation with interferon gamma (IFN-γ) alone or in combination with TLR ligands (e.g. lipopolysaccharide (LPS)) whereas macrophages acquire M2 phenotype after in vitro exposure to IL-4 and IL-13. M1 macrophages secrete high levels of proinflammatory cytokines (e.g. tumor necrosis factor (TNF-α), IL-6, IL-1β) and generate reactive oxygen and nitrogen species such as nitric oxide via activation of inducible nitric oxide synthase (iNOS). Conversely, M2 macrophages activate arginase 1 (Arg1) that blocks iNOS activity and therefore inhibits nitric oxide production. They also secrete anti-inflammatory cytokines (e.g. IL-10, TGF-β, IL-4) essential for inflammatory response resolution. M1 macrophages are microbicidal and tumoricidal, and stimulate adaptive immune response. M2 macrophages are associated with anti-inflammatory and homeostatic functions linked to wound healing. However, in this classification system, M1 and M2 macrophages are regarded as two extreme phenotypes. For example, macrophages stimulated with IL-4 and IL-13 are defined as M2a, whereas macrophages stimulated with LPS and apoptotic cells as M2b and macrophages stimulated with IL-10, transforming growth factor-β (TGF-β) or glucocorticoids as M2c. In adipose tissue, distinction between M1 and M2 macrophage polarization can be monitored by assessing the expression of selected markers. Macrophages displaying M1 phenotype have been characterized by expression of F4/80, CD11c and iNOS whereas macrophages displaying M2 phenotype have been characterized by expression of F4/80, CD301 and Arg1.

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