Dendritic Cells in Subcutaneous and Epicardial Adipose Tissue of Subjects with Type 2 Diabetes, Obesity, and Coronary Artery Disease

Abstract

Dendritic cells (DCs) are professional antigen-presenting cells contributing to regulation of lymphocyte immune response. DCs are divided into two subtypes: CD11c-positive conventional or myeloid (cDCs) and CD123-positive plasmacytoid (pDCs) DCs. The aim of the study was to assess DCs (HLA-DR+ lineage-) and their subtypes by flow cytometry in peripheral blood and subcutaneous (SAT) and epicardial (EAT) adipose tissue in subjects with (T2DM, n=12) and without (non-T2DM, n=17) type 2 diabetes mellitus undergoing elective cardiac surgery. Subjects with T2DM had higher fasting glycemia (8.6±0.7 vs. 5.8±0.2 mmol/l, p<0.001) and glycated hemoglobin (52.0±3.4 vs. 36.9±1.0 mmol/mol, p<0.001) and tended to have more pronounced inflammation (hsCRP: 9.8±3.1 vs. 5.1±1.9 mg/ml, p=0.177) compared with subjects without T2DM. T2DM was associated with reduced total DCs in SAT (1.57±0.65 vs. 4.45±1.56% for T2DM vs. non-T2DM, p=0.041) with a similar, albeit insignificant, trend in EAT (0.996±0.33 vs. 2.46±0.78% for T2DM vs. non-T2DM, p=0.171). When analyzing DC subsets, no difference in cDCs was seen between any of the studied groups or adipose tissue pools. In contrast, pDCs were increased in both SAT (13.5±2.0 vs. 4.6±1.9% of DC cells, p=0.005) and EAT (29.1±8.7 vs. 8.4±2.4% of DC, p=0.045) of T2DM relative to non-T2DM subjects as well as in EAT of the T2DM group compared with corresponding SAT (29.1±8.7 vs. 13.5±2.0% of DC, p=0.020). Neither obesity nor coronary artery disease (CAD) significantly influenced the number of total, cDC, or pDC in SAT or EAT according to multiple regression analysis. In summary, T2DM decreased the amount of total dendritic cells in subcutaneous adipose tissue and increased plasmacytoid dendritic cells in subcutaneous and even more in epicardial adipose tissue. These findings suggest a potential role of pDCs in the development of T2DM-associated adipose tissue low-grade inflammation.

Shaping of Dendritic Cell Function by the Metabolic Micro-Environment

“…Hence, it is perhaps somewhat surprising that ex vivo data indicate that hyperglycemia has minimal effect on the function of DCs, that most in vitro studies describe a tolerogenic effect of excessive glucose levels on DC differentiation, and that only in vitro mature DCs are likely to become more proinflammatory. Although currently it cannot be excluded that the latter observations may be due the use of in vitro model systems, such as in vitro generated moDCs that possibly cannot sufficiently mimic the metabolic alterations and glucose-rich environment that cDCs and pDCs are exposed to in vivo, it may in fact indicate that hyperglycemia is not a major driver of the pro-inflammatory profiles of DCs observed in diabetes and that other metabolic and/or immunological cues are more important (62,(130)(131)(132). This idea would be consistent with the fact that hyperglycemia is generally associated with impaired immune response against for example infections and tumors (149,150).…”

“…This causes a switch in the composition and phenotype of immune cells in metabolic tissues from an anti-inflammatory to a more pro-inflammatory profile and thereby induces chronic low-grade inflammation, which ultimately drives insulin resistance (127)(128)(129). cDCs and pDCs are among the immune cells present in adipose tissue and there is a clear correlation between insulin resistance and number of CD11c + DCs present in adipose tissue (62,(130)(131)(132). Moreover, several studies have shown that in response to high-fat diet DCs present in murine adipose tissue transition from Th1-to Th17priming cells, an inflammatory profile linked to the pathogenesis of diabetes (62,63,133).…”

Dietary Fatty Acids in Postprandial Triglyceride-Rich Lipoproteins Modulate Human Monocyte-Derived Dendritic Cell Maturation and Activation

“…These leukocytes are the first immune cells that respond quickly to injury and their activation, if permanent or chronic, may cause the increase of the inflammatory response, the perpetuation of the inflammatory state and the development of obesity or autoimmune disease [ 26 , 27 ]. DCs are professional antigen-presenting cells within the immune system, that are uniquely capable of priming naïve T cells, and once activated they have a pivotal ability to induce primary innate and adaptive immune response [ 28 ]. However, little is known about the effect of dietary fatty acids on human moDC [ 29 ].…”

Brown adipose tissue ameliorates autoimmune arthritis via inhibition of Th17 cells

“…Adipose tissue constitutes the major source of cytokines, chemokines, and metabolically active mediators known as adipokines 6 , 7 . It has been suggested that inflammation, which is induced by adipose tissue, is associated with osteoarthritis 8 – 10 , rheumatoid arthritis (RA) 11 – 13 , type 2 diabetes mellitus 14 – 17 , and coronary artery disease 18 , 19 .…”