CCL17 and CCL22 chemokines are upregulated in human obesity and play a role in vascular dysfunction

Abstract

Background/AimsChemokines are known to play critical roles mediating inflammation in many pathophysiological processes. The aim of this study was to investigate the role of chemokine receptor CCR4 and its ligands CCL17 and CCL22 in human morbid obesity.MethodsCirculating levels of CCL17 and CCL22 were measured in 60 morbidly obese patients (mean age, 45 ± 1 years; body mass index/BMI, 44 ± 1 kg/m2) who had undergone bariatric bypass surgery, and 20 control subjects. Paired subcutaneous (SCAT) and visceral adipose tissue (VCAT) from patients were analysed to measure expression of CCR4 and its ligands by RT-PCR, western blot and immunohistochemical analysis. The effects of CCR4 neutralization ex vivo on leukocyte-endothelial cells were also evaluated.ResultsCompared with controls, morbidly obese patients presented higher circulating levels of CCL17 (p=0.029) and CCL22 (p<0.001) and this increase was positively correlated with BMI (p=0.013 and p=0.0016), and HOMA-IR Index (p=0.042 and p< 0.001). Upregulation of CCR4, CCL17 and CCL22 expression was detected in VCAT in comparison with SCAT (p<0.05). Using the parallel-plate flow chamber model, blockade of endothelial CCR4 function with the neutralizing antibody anti-CCR4 in morbidly obese patients significantly reduced leucocyte adhesiveness to dysfunctional endothelium, a key event in atherogenesis. Additionally, CCL17 and CCL22 increased activation of the ERK1/2 mitogen-activated protein kinase signalling pathway in human aortic endothelial cells, which was significantly reduced by CCR4 inhibition (p=0.016 and p<0.05).ConclusionBased on these findings, pharmacological modulation of the CCR4 axis could represent a new therapeutic approach to prevent adipose tissue dysfunction in obesity.

Dawn-to-dusk dry fasting decreases circulating inflammatory cytokines in subjects with increased body mass index

“…A significant decrease in the mean levels of several other cytokines was observed including IL-15 (P = 0.014), IL-1ra (P = 0.041), MDC (P = 0.013), and MIG/CXCL9 (P = 0.027) within the fourth week of 30-day DDDF, and IL-12p40 (P = 0.038) and IL-22 (P = 0.025) within two weeks after 30-day DDDF compared with the baseline levels of these cytokines ( Table 2 ). Increased levels of these inflammatory cytokines were reported to be involved in the low-grade chronic inflammation of obesity and its complications [ [64] , [65] , [66] , [67] , [68] , [69] ]. IL-15 is a proinflammatory cytokine implicated in the development of insulin resistance and hepatic steatosis [ [64] , [65] ].…”

“…Likewise, IL-1ra levels were shown to be elevated in subjects with morbid obesity and improved after bariatric surgery [ 66 ]. MDC, also known as CCL22, was upregulated in obesity and linked to endothelial dysfunction [ 67 , 68 ]. A study showed that, in contrast to mice fed by regular chow diet, mice fed by methionine/choline-deficient diet had metabolic dysfunction-associated steatohepatitis, and significantly increased MIG/CXCL9 levels that contributed to an imbalance in the regulatory T cell to T helper 17 ratio by suppressing regulatory T cell and increasing T helper 17 cell proliferation [ 69 ].…”