Adiponectin Promotes Macrophage Polarization toward an Anti-inflammatory Phenotype

Abstract

It is established that the adipocyte-derived cytokine adiponectin protects against cardiovascular and metabolic diseases, but the effect of this adipokine on macrophage polarization, an important mediator of disease progression, has never been assessed. We hypothesized that adiponectin modulates macrophage polarization from that resembling a classically activated M1 phenotype to that resembling alternatively-activated M2 cells. Peritoneal macrophages and the stromal vascular fraction (SVF) cells of adipose tissue isolated from adiponectin knock-out mice displayed increased M1 markers, including tumor necrosis factor-␣, interleukin-6, and monocyte chemoattractant protein-1 and decreased M2 markers, including arginase-1, macrophage galactose N-acetyl-galactosamine specific lectin-1, and interleukin-10. The systemic delivery of adenovirus expressing adiponectin significantly augmented arginase-1 expression in peritoneal macrophages and SVF cells in both wild-type and adiponectin knock-out mice. In culture, the treatment of macrophages with recombinant adiponectin protein led to an increase in the levels of M2 markers and a reduction of reactive oxygen species and reactive oxygen species-related gene expression. Adiponectin also stimulated the expression of M2 markers and attenuated the expression of M1 markers in human monocyte-derived macrophages and SVF cells isolated from human adipose tissue. These data show that adiponectin functions as a regulator of macrophage polarization, and they indicate that conditions of high adiponectin expression may deter metabolic and cardiovascular disease progression by favoring an anti-inflammatory phenotype in macrophages.Obesity activates low grade inflammation that contributes to the pathogenesis of obesity-linked diseases, such as type 2 diabetes and atherosclerosis (1). Adipose tissue macrophages play an important role in the establishment of the chronic inflammatory state and metabolic dysfunction that is associated with obesity (2, 3). Recent findings show that adipose tissue macrophages from lean organisms express markers of the M2 or "alternatively activated" macrophage, whereas obesity leads to a reduction of these markers and an increase of genes associated with the M1 or "classically activated" macrophage (4). M1 macrophage polarization is associated with inflammation and tissue destruction, whereas the M2 macrophage has an anti-inflammatory phenotype that is associated with wound repair and angiogenesis.Macrophages are polarized to the M1 state by interferon-␥ and inducers of tumor necrosis factor-␣ (TNF-␣) 2 , such as lipopolysaccharide (LPS). M1 macrophages up-regulate proinflammatory cytokines including TNF-␣, interleukin (IL)-6, and IL-12, and they increase the production of reactive oxygen species (ROS) and nitrogen intermediates (5). In contrast, macrophages are polarized to the M2 state by IL-4 and IL-13. M2 macrophages up-regulate scavenger receptors, mannose receptor and IL-1 receptor antagonist. M2 cells also secrete the antiinflammatory cytokine IL-10 and...

Adiponectin regulates psoriasiform skin inflammation by suppressing IL-17 production from γδ-T cells

“…We observed that adiponectin deficiency resulted in severe psoriasiform inflammation. Since it is widely known that inhibition of adiponectin upregulates TNF-a production from macrophages or adipocytes 25,43 , we expected that the increased skin inflammation in adiponectin-deficient mice was mainly due to the overexpression of TNF-a. Although TNF-a expression was indeed elevated in the inflamed skin of adiponectin-deficient mice, even more striking was the upregulated expression of Th17-related cytokines, IL-17A/IL-17F/IL-22.…”

“…Interestingly, recent reports regarding adiponectin have been focusing on a new feature of adiponectin, an aspect as a regulator of immune responses 22,23 . A number of experimental studies suggest that adiponectin attenuates excessive inflammatory responses in a variety of tissues, especially in obesity-associated states [24][25][26] . Roles of adiponectin in the development of psoriasis, one of the obesitylinked diseases as mentioned above, have been also discussed in the vast past epidemiologic reports [27][28][29] .…”

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

“…Adiponectin knockout mice display moderate insulin resistance in the liver and impaired glucose tolerance [32], and have activated macrophages in AT with increased secretion of proinflammatory cytokines such as MCP-1 compared with macrophages of wild-type mice [17,33]. Adiponectin knockout mice also appear to have more hepatic steatosis and activated Kupffer cells than wild-type mice [34,35].…”

Importance of adiponectin activity in the pathogenesis of Alzheimer's disease

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