Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production

Abstract

Objective: Obesity is associated with a chronic low-grade inflammation and an increased abundance of macrophages in adipose tissue. Adipose tissue macrophages (ATMs) are assumed to interfere with adipocyte function leading to insulin resistance, thereby contributing to the pathogenesis of type 2 diabetes mellitus. Macrophages exist in separate types of differentiation, but the nature of ATMs is largely unknown. Design and measurements: Stromal vascular cells (SVCs) and ATMs were isolated from human adipose tissues from different locations. We characterized ATMs phenotypically and functionally by flow cytometry, endocytosis assay and determination of secreted cytokines. For comparison, we used macrophages of the 'classical' (M1) and the 'alternative', anti-inflammatory (M2) type differentiated in vitro from peripheral blood monocytes. Results: Like prototypic M2 macrophages, ATMs expressed considerable amounts of mannose receptor, haemoglobin scavenger receptor CD163 and integrin avb5. The number of cells expressing these molecules correlated significantly with the donors' body mass indices (BMIs). Notably, SVCs positive for the common monocyte/macrophage marker CD14 contained a considerable fraction of blood monocytes, the abundance of which did not correlate with the BMIs, pointing to the requirement of the surface markers identified here for the identification of ATMs. ATMs showed endocytic activities similar to M2 macrophages and accordingly secreted high amounts of IL-10 and IL-1 receptor antagonist. However, basal and induced secretion of pro-inflammatory mediators TNF-a, IL-6, IL-1, MCP-1 and MIP-1a was even higher in ATMs than in proinflammatory M1 macrophages. Conclusion: ATMs comprise a particular macrophage type that is M2-like by surface marker expression, but they are competent to produce extensive amounts of inflammatory cytokines, which could considerably contribute to the development of insulin resistance.

Diminished upregulation of visceral adipose heme oxygenase-1 correlates with waist-to-hip ratio and insulin resistance

“…This finding is somewhat surprising, as factors inducing CD163 such as interleukin-6 and tumor necrosis factor-a are elevated in the obese adipose tissue, but are in accordance with previous data on CD163 surface expression, which did not correlate with BMI in a small cross-sectional study. 10 One explanation could be that CD163 expression is already very high in adipose tissue macrophages of lean individuals. 10 However, so far very little is known about molecules regulated by obesity in human in contrast to murine adipose tissue macrophages, 13,43 and thus our results on HMOX1 indicating marked regulation in macrophages upon visceral obesity (Figure 2d) is of particular interest and warrants further investigation.…”

“…10 One explanation could be that CD163 expression is already very high in adipose tissue macrophages of lean individuals. 10 However, so far very little is known about molecules regulated by obesity in human in contrast to murine adipose tissue macrophages, 13,43 and thus our results on HMOX1 indicating marked regulation in macrophages upon visceral obesity (Figure 2d) is of particular interest and warrants further investigation. Such studies may also elucidate whether heme oxygenase-1 is regulate dependent or independent of CD163.…”

“…5,6 Obesity-associated adipose tissue inflammation is characterized by an increased abundance of adipose tissue macrophages in mice; 6,7 several studies have confirmed a correlation between body mass index (BMI) and adipose tissue macrophage numbers in humans particularly in the metabolically relevant visceral adipose tissue. [8][9][10][11] Therefore, adipose tissue macrophages are assumed to critically contribute to the pathogenesis of type 2 diabetes mellitus and the metabolic syndrome by driving obesity-associated chronic inflammation. In contrast, adipose tissue macrophages may also have cytoprotective anti-inflammatory properties, as identified by the expression of several markers that determine an alternatively activated, anti-inflammatory macrophage type, 12,13 for instance, the hemoglobin scavenger receptor CD163.…”

“…In contrast, adipose tissue macrophages may also have cytoprotective anti-inflammatory properties, as identified by the expression of several markers that determine an alternatively activated, anti-inflammatory macrophage type, 12,13 for instance, the hemoglobin scavenger receptor CD163. 10,14 CD163 is exclusively expressed on monocytes and macrophages and mediates endocytosis of haptoglobinhemoglobin complexes, 15 thereby preventing oxidative and nitrosative toxicity emerging upon red blood cell hemolysis. 16 Moreover, CD163-mediated uptake of hemoglobin into the macrophage fuels an anti-inflammatory response driven by heme oxygenase-1 activity, leading to potent anti-inflammatory heme metabolites.…”

The maternal and fetal impacts of obesity and gestational diabetes on pregnancy outcome

“…Numerous studies show increased circulating proinflammatory cytokines. 5,[66][67][68] Additionally, the non-specific marker of inflammation, C-reactive protein (CRP) is raised and the anti-inflammatory adipokine, adiponectin, reduced. These serum markers of inflammation are associated with a poor metabolic profile, type 2 diabetes and gestational diabetes.…”