TABLE 2 - uploaded by Vlatka Pandzic Jaksic
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Corre elations o of monoc cyte activ vation varia ables
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Purpose:
Monocytes actively participate in inflammatory mechanisms that contribute to the development of adipose tissue dysfunction and atherogenesis. The aim of this study was to evaluate the association of monocyte CCR2 chemokine receptor expression and intracellular oxidative burst with the metabolic and inflammatory factors related to body wei...
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Crescents are morphologic manifestations of severe glomerular injury. Several chemokines and their receptors have been demonstrated to be involved in animal models of crescentic glomerulonephritis (cGN) and are potential targets for therapeutic interventions. Therefore, the expression of monocyte chemoattractant protein-1 (MCP-1), its receptor chem...
Citations
... Insulin downregulates the HSL activity in peritoneal macrophages [44]. The number of monocytes and the monocyte activation markers are significantly associated with obesity and insulin resistance [45]. Perhaps HSL in fat and plasma act via different mechanisms, which could be a driving direction for future research. ...
Zinc α2-glycoprotein (ZAG) has been implicated in fatty acid metabolism and utilization and is lower in obese and higher in cachexic adults compared to those of normal weight. Previous studies suggest that ZAG binds to the beta3-adrenergic receptor (β3AR) to influence fatty acid metabolism in adipose tissue by regulating hormone sensitive lipase (HSL). The purpose of this study is to investigate the effects of a six-month weight loss (WL) or aerobic exercise (AEX) intervention on adipose tissue and skeletal muscle ZAG mRNA levels and protein expression, as well as the expression of β3AR, and HSL. Abdominal adipose tissue (AB) and gluteal adipose tissue (Glut) and vastus lateralis muscle biopsies were performed before and after WL (n = 13) or AEX (n = 13). ZAG, HSL, and β3AR expressions were determined by RT-PCR, and ZAG and HSL plasma levels by ELISA. Body weight decreased by 9.69% (p < 0.001) in WL and did not change with AEX. Maximal oxygen consumption (VO2max) increased by 7.1% (p < 0.005) after WL and by 16.69% (p < 0.001) after AEX. WL significantly decreased body weight with a reduction of percentage of fat, fat mass, fat-free mass (FFM). AEX decreased percent fat and increased VO2max, but did not change fat mass and FFM. Abdominal ZAG and HSL mRNA levels did not change significantly after WL or AEX. There were no changes in plasma ZAG, HSL and adipose tissue β3AR mRNA levels after WL and AEX. ZAG, HSL and β3AR mRNA expressions in adipose tissue are positively associated each other. Adipose tissue abdominal and gluteal HSL are negatively associated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), and both ZAG and HSL adipose tissue are negatively associated with fasting glucose and the glucose area under the curve. Further work is needed to elucidate the role of ZAG and HSL in the propensity for weight gain and the ability of exercise to mitigate these responses.
... The association of systemic inflammation and insulin resistance in both PWH and HIV-negative individuals has been extensively reported in the literature [10,11,29,30], but the adaptive immune system has recently emerged as a potential contributor to metabolic dysregulation [31][32][33]. In the largest and most comprehensive assessment of T-cell subsets and diabetes to date, we show that expansion of memory CD4 + T cells is associated with prevalent diabetes in both PWH and HIVnegative persons. ...
Background:
A higher proportion of circulating memory CD4+ T cells is associated with prevalent diabetes mellitus in the general population. Given the broad changes in adaptive immunity, including memory T cell expansion, and rising prevalence of diabetes in the HIV population, we assessed whether similar relationships were present in persons with HIV (PWH).
Methods:
Multiple CD4+ and CD8+ T cell subsets were measured by flow cytometry and prevalent diabetes cases were adjudicated by two physicians for PWH and HIV-negative participants in the Veterans Aging Cohort Study. Multivariable logistic regression models evaluated the association of T cell subsets and diabetes stratified by HIV status, adjusted for cytomegalovirus serostatus and traditional risk factors.
Results:
Among 2385 participants (65% PWH, 95% male, 68% African American), higher CD45RO+ memory CD4+ T cells and lower CD38+ CD4+ T cells were associated with prevalent diabetes, and had a similar effect size, in both the PWH and HIV-negative (p<0.05 for all). Lower CD38+ CD8+ T cells were also associated with diabetes in both groups.
Conclusions:
The CD4+ and CD8+ T cell subsets associated with diabetes are similar in PWH and HIV-negative individuals, suggesting that diabetes in PWH may be related to chronic immune activation.
... The involvement of the MCP-1/chemokine receptor 2 (CCR2) pathway has been extensively studied as the mechanism underlying macrophage infiltration into obese AT [4,56]. Circulating and AT levels of MCP-1 and levels of CCR2-expressing inflammatory cells are increased in obesity, and are strongly associated with IR [57,58]. MCP-1 is also crucially involved in monocyte/macrophage recruitment into the arterial wall, a major process leading to atherosclerosis [59], thus providing a possible causative link between obesity and related complications, such as CVD. ...
Chronic inflammation of the adipose tissue (AT) is a major contributor to obesity-associated cardiometabolic complications. The olive oil polyphenol hydroxytyrosol (HT) contributes to Mediterranean diet cardiometabolic benefits through mechanisms still partially unknown. We investigated HT (1 and 10 μmol/L) effects on gene expression (mRNA and microRNA) related to inflammation induced by 10 ng/mL tumor necrosis factor (TNF)-α in human Simpson–Golabi–Behmel Syndrome (SGBS) adipocytes. At real-time PCR, HT significantly inhibited TNF-α-induced mRNA levels, of monocyte chemoattractant protein-1, C-X-C Motif Ligand-10, interleukin (IL)-1β, IL-6, vascular endothelial growth factor, plasminogen activator inhibitor-1, cyclooxygenase-2, macrophage colony-stimulating factor, matrix metalloproteinase-2, Cu/Zn superoxide dismutase-1, and glutathione peroxidase, as well as surface expression of intercellular adhesion molecule-1, and reverted the TNF-α-mediated inhibition of endothelial nitric oxide synthase, peroxisome proliferator-activated receptor coactivator-1α, and glucose transporter-4. We found similar effects in adipocytes stimulated by macrophage-conditioned media. Accordingly, HT significantly counteracted miR-155-5p, miR-34a-5p, and let-7c-5p expression in both cells and exosomes, and prevented NF-κB activation and production of reactive oxygen species. HT can therefore modulate adipocyte gene expression profile through mechanisms involving a reduction of oxidative stress and NF-κB inhibition. By such mechanisms, HT may blunt macrophage recruitment and improve AT inflammation, preventing the deregulation of pathways involved in obesity-related diseases.
... Inflammation has been considered the link among obesity and the higher risk of cardiovascular and metabolic complications (Lumeng and Saltiel, 2011;Mathieu et al., 2010) and therefore modification of the inflammatory milieu in obesity can be of clinical significance for individuals with obesity. One hallmark of inflammation in obesity is the excessive accumulation of macrophages in the adipose tissue (Lumeng et al., 2007), which is generally associated with activation of circulating monocytes (Minervino et al., 2015;Pandzic Jaksic et al., 2013). ...
Alterations in the distribution and activation of monocyte subsets are frequently observed in individuals with obesity and their participation in the pathological complications of obesity is proposed. High-intensity interval training (HIIT) can be a time-efficient alternative to counteract the inflammatory outcomes of obesity, but so far, its effects on monocytes in obesity has not been fully explored. In this study, we investigated whether 8 weeks of HIIT can modify the distribution and activation of the three monocyte subsets (classical, intermediate and non-classical monocytes) in individuals with obesity. Our data show that individuals with obesity have a higher percentage of non-classical monocytes compared to control, lean individuals, and consequently an imbalance among the CD16+ monocyte subsets. Also, the expression of HLA-DR by intermediate monocytes is higher in insulin-resistant obese individuals, which indicates monocyte activation in obesity. After 8 weeks of HIIT, the percentage of non-classical monocytes was reduced in individuals with obesity, restoring the balance among the CD16+ monocytes. Also, the expression of HLA-DR by intermediate monocytes in insulin-resistant obese subjects was lower after HIIT. Both findings indicate that monocyte activation in individuals with obesity was reduced by HIIT. These modifications were observed in the absence of changes in weight and body composition, although they were accompanied by the improvement in the metabolic status (reduced insulin levels). Our findings indicate that HIIT can be considered a time-efficient strategy to manage obesity-related monocyte alterations and strengthen the immunomodulatory potential of HIIT.
... It was shown that vascular injury was in part dependent on MCP-1 released locally by the adipose tissue. MCP-1, as an inflammatory adipokine [41], was secreted 10-40 times more in PVAT than in SAT from same subjects [42], [43]. On the other hand, adiponectin, as the main antiinflammatory adipokine, is reduced in obesity and similar conclusions were derived from experiments with PVAT from adiponectin knockout mice (APN−/−). ...
Upper body adipose tissue accumulation has been associated with clustering of metabolic disorders and increased cardiovascular risk. Neck circumference (NC) indicated that subcutaneous adipose tissue (SAT) in that region is an independent pathogenic depot that might account for the additional risk missed by visceral adipose tissue (VAT). Neck adipose tissue (NAT) is not only one more ectopic depot but has several particular features that might modulate its metabolic role. Besides a controversial impact on obstructive apnea syndrome, neck fat encompasses carotid arteries as an important perivascular adipose tissue (PVAT) depot. With dysfunctional changes in obesity, physiologic vascular regulation is lost and inflammatory signals accelerate atherogenesis. Unexpected was the discovery of brown and beige adipocytes in the neck of human adults. When stimulated, brown adipose tissue (BAT) dissipates energy through thermogenesis and it is associated with other favorable metabolic effects. Moreover, the neck is the region where the browning mechanism was disclosed. With this unique plastic nature, NAT revealed multiple ties, challenging dynamics and potential new therapeutic targets that might have significant implications on metabolic outcomes and vascular risk.
... Adipose tissue and altered lipid metabolism contribute to increased systemic inflammation 40 . We found BMI was positively correlated with the expression of CCR2 on classical monocytes, which is consistent with previous data showing BMI and fat mass correlate with increased expression of CCR2 on monocytes 41 . Thus, adiposity may accelerate the CCR2mediated infiltration of monocytes to the synovium where they contribute to pathogenesis (i.e., pain, cartilage erosion). ...
Background:
Exercise may help to mitigate symptoms of depression by reducing inflammation; however, little is known about the influence of exercise intensity on depressed mood.
Methods:
In the present study, sixty-one university students were assigned to six weeks of high-intensity interval training (HIT), moderate continuous training (MCT), or no exercise (CON) during their academic term. We measured changes in depression, anxiety and perceived stress along with pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and C-reactive protein (CRP).
Results:
Depression increased for CON, demonstrating how quickly mental health can decline for students during their academic term. In contrast, MCT decreased depression and pro-inflammatory cytokine TNF-α levels. Although HIT decreased depressive symptoms, it also increased perceived stress, TNF-α and IL-6 relative to MCT. This may be due to the higher level of physical stress evoked by the more strenuous exercise protocol.
Conclusions:
Taken together, the results suggest that moderate-intensity exercise may be an optimal intensity of exercise for the promotion of mental health by decreasing TNF-α. This is critical for informing the use of exercise as medicine for mental health.
... Adipose tissue and altered lipid metabolism contribute to increased systemic inflammation 40 . We found BMI was positively correlated with the expression of CCR2 on classical monocytes, which is consistent with previous data showing BMI and fat mass correlate with increased expression of CCR2 on monocytes 41 . Thus, adiposity may accelerate the CCR2- mediated infiltration of monocytes to the synovium where they contribute to pathogenesis (i.e., pain, cartilage erosion). ...
Objective:
Monocytes contribute to synovitis and disease pathogenesis in OA. Low-grade inflammation occurs in OA and correlates with disease severity and progression. Since monocyte development and function is altered by systemic inflammation, we analyzed monocyte numbers and function between individuals with knee OA and healthy age- and sex-matched controls.
Design:
We analyzed markers of soluble and cellular inflammation in peripheral blood of women with knee OA and compared them to healthy age- and sex-matched controls. Soluble inflammatory mediators (TNF, IL-6, IL-10 and CRP) in the serum were measured by high-sensitivity ELISA. Leukocyte numbers, surface expression of monocyte activation markers, and monocyte production of pro-inflammatory mediators (TNF and IL-1β) following stimulation were measured by flow cytometry.
Results:
Women with knee OA (n=15) had elevated levels of serum CRP and a lower proportion of circulating monocytes. Monocytes from OA participants had elevated expression of the activation markers CD16, CCR2, and HLA-DR and induced greater production of TNF and IL-1β compared to healthy controls. Higher serum TNF and BMI were correlated with increased monocyte expression of CCR2. Additionally monocyte CCR2 expression and serum TNF were correlated with worse pain on a validated questionnaire.
Conclusions:
Our findings suggest monocytes are activated prior to their entry into the synovium. Modulating systemic inflammation and monocyte recruitment to the synovium could be of therapeutic benefit.
... Growth of adipose tissue might not be followed by adequate angiogenesis, and local hypoxia might cause adipocyte apoptosis and necrosis. Obese adipocytes release higher amounts of free fatty acids and proinflammatory adipocytokines but less adiponectin (30)(31)(32)(33). In response to these signals, a basic inflammatory mechanism is initiated with the activation of monocytes, their migration, and recruitment of macrophages. ...
The global obesity epidemic enhanced contemporary interest in adi-pose tissue biology. Two structurally and functionally distinct depots, subcutane-ous adipose tissue (SAT) and visceral adipose tissue (VAT), are spread throughout the body. Their distribution was recognized to be a major determinant of metabolic risk. Unlike VAT, SAT showed some protective endocrine and inflammatory features that might explain the occurrence of obese but metabolically healthy persons. The unique developmental gene expression signature, angiogenesis, and adipogenic potential of SAT determines its growth ability under the positive energy balance. The overflow hypothesis suggested that when SAT is unable to expand sufficiently, fat overflows towards metabolically adverse ectopic depots. Besides white adipose tissue, recent studies found important brown adipose tissue activity responsible for thermogenesis and energy dissipation in adults as well. SAT is prone to " browning " – the appearance of particular beige adipocytes that contribute to its favorable metabolic effects. Morbid obesity, aging, hormonal status, nutrition, low physical activity, and other environmental factors impair SAT relative resistance to dysfunc-tional changes and promote development of metabolic disorders. The popular approach considering SAT mainly as the subject of cosmetic procedures for improving the appearance of body contours should be avoided. Complex heterogeneity of obesity revealed that a tissue of an extreme plasticity and rich interactions with vital functions of the body lies under the surface. Therapeutic manipulations to preserve and enhance healthier fat in order to correct obesity-related metabolic disorders seem to be a relevant but still unexplored opportunity.
... 24 In the general population, increases in circulating monocytes have been observed in diabetic subjects compared to non-diabetic controls. [26][27][28] CD16-bearing monocyte subsets have been reported to be increased in patients with type 2 diabetes and in particular in those with diabetic complications such as renal disease. 13,26,29 We have reported that increases in insulin resistance are associated with increases in circulating monocytes in HIV-infected subjects Taken together, these data indicate a potentially important role for monocyte populations in the pathogenesis of HIV-associated cardio-metabolic disorders. ...
Background:
Inflammation may contribute to cardiovascular disease (CVD) among antiretrovirally suppressed HIV-infected individuals. We assessed relationships of monocyte, CD8 T-cell activation and plasma biomarkers to changes in carotid artery intima-media thickness (CIMT).
Methods:
Longitudinal study of HIV-infected subjects ≥40 years and on stable antiretroviral therapy (ART) ≥3 months. Peripheral blood mononuclear cells were immunophenotyped by multiparameteric flow cytometry to quantify classical (CD14(++)CD16(-)), intermediate (CD14(++)CD16(+)), non-classical (CD14(low/+)CD16(++)) and transitional (CD14(+)CD16(-)) monocyte subsets and activated (CD38(+)HLA-DR(+)) CD8(+) T-cells at baseline. Plasma biomarkers were assessed by multiplex Luminex assay. High-resolution B-mode ultrasounds of right carotid arteries were obtained. Changes in CIMT over two years at the right common carotid artery (CIMTCCA) and right bifurcation (CIMTBIF) were outcome variables.
Results:
We studied 50 subjects: 84% male, median age 49 (Q1, Q3; 46, 56) years, median CD4 count 461 (317, 578) cells/mm(3), and with HIV RNA ≤ 50 copies/mL in 84%. Change in CIMTBIF correlated with log values of baseline absolute count of non-classical monocytes (r = 0.37, p = 0.020), and with MCP-1 (r = 0.42, p = 0.0024) and TNF-α (r = 0.30, p = 0.036) levels. In multivariable linear regression, only non-classical monocytes and MCP-1 predicted the change in CIMTBIF, independent of Framingham Risk Score and baseline CIMTBIF. No correlation was noted between CD8 T-cell activation and CIMTBIF change. Monocyte subsets, CD8 T-cell activation, and biomarker concentrations were not correlated with changes in CIMTCCA.
Conclusions:
Our findings highlight the role of non-classical monocytes and MCP-1 in the progression of CIMTBIF in HIV-infected individuals on stable ART independent of traditional cardio-metabolic risk factors.
... [24][25][26][27][28][29] Increased levels of MCP-1 in plasma and subcutaneous AT and elevated levels of CCR2expressing inflammatory cells in AT of obese human subjects are strongly associated with insulin resistance. 24,[28][29][30][31][32] These observations implicate MCP-1 in the recruitment of macrophages to the AT and in the development of insulin resistance in obese humans and rodents through similar mechanisms. Mice deficient in CCR2 display lower inflammation in AT and have a reduced propensity to develop insulin resistance while mice overexpressing MCP-1 have an exacerbated insulin resistance phenotype. ...
... Mice deficient in CCR2 display lower inflammation in AT and have a reduced propensity to develop insulin resistance while mice overexpressing MCP-1 have an exacerbated insulin resistance phenotype. 24,25,29,32 CCR2 is also a receptor for other chemokines such as CCL7 (MCP-3), CCL8 (MCP-2), CCL12 (MCP-5), and CCL13 (MCP-4) that are all increased in inflamed obese AT. 7,25,33 Thus, blockade/reduction of CCR2 expression in macrophages may disrupt their chemotaxis to the AT and reduce the downstream effects of obesity-induced inflammation. ...
Adipose tissue macrophage (ATM)-mediated inflammation is a key feature contributing to the adverse metabolic outcomes of dietary obesity. Recruitment of macrophages to obese adipose tissues (AT) can occur through the engagement of CCR2, the receptor for MCP-1 (monocyte chemoattractant protein-1), which is expressed on peripheral monocytes/macrophages. Here, we show that i.p. administration of a rabies virus glycoprotein-derived acetylcholine receptor-binding peptide effectively delivers complexed siRNA into peritoneal macrophages and ATMs in a mouse model of high-fat diet-induced obesity. Treatment with siRNA against CCR2 inhibited macrophage infiltration and accumulation in AT and, therefore, proinflammatory cytokines produced by macrophages. Consequently, the treatment significantly improved glucose tolerance and insulin sensitivity profiles, and also alleviated the associated symptoms of hepatic steatosis and reduced hepatic triglyceride production. These results demonstrate that disruption of macrophage chemotaxis to the AT through cell-targeted gene knockdown strategies can provide a therapeutic intervention for obesity-related metabolic diseases. The study also highlights a siRNA delivery approach for targeting specific monocyte subsets that contribute to obesity-associated inflammation without affecting the function of other tissue-resident macrophages that are essential for host homeostasis and survival.
