Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome

Summary

Principal Investigator: Huaizhu Wu
Abstract: DESCRIPTION (provided by applicant): Obesity increases risk for diabetes and atherosclerotic cardiovascular disease (CVD). However, the underlying mechanisms remain poorly understood. It is currently known that obesity is associated with chronic inflammation-characterized by increased production and secretion of cytokines/chemokines by adipose tissue (AT) and liver-and with increased hepatic production of triglyceride-rich lipoproteins (TGRLs) and increased levels of fatty acids (FAs, saturated FAs in particular). Current data suggest that these changes activate leukocytes in blood and AT. Blood monocyte activation can increase monocyte adhesion and migration, which is implicated in the development of atherosclerosis and accelerates inflammation in AT. Leukocyte accumulation and activation in AT may be critical to the development of adverse metabolic and pathogenic effects of obesity. CD11c is a b2 integrin primarily expressed on monocytes/macrophages and dendritic cells (DCs) that is a marker for monocyte/macrophage activation and participates in monocyte recruitment. Our preliminary data show that: (1) obesity with insulin resistance induced by high-fat (HF) diet rich in saturated FAs up-regulates CD11c on blood monocytes and AT macrophages;(2) CD11c contributes to monocyte adhesion and migration on inflamed endothelial cells (ECs) by binding vascular cell adhesion molecule-1 (VCAM-1);and (3) deficiency of CD11c in obese mice reduces atherosclerosis and decreases AT inflammation. Therefore, we hypothesize that obesity is associated with monocyte activation with increased CD11c expression, and that CD11c is mechanistically linked to obesity-related diseases including CVD and diabetes. Three specific aims are proposed to test our hypotheses: Aim 1. Examine blood monocyte activation, including CD11c expression, in obese mice and humans;and its modulation by weight loss and by dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA);Aim 2. Determine the role of increased CD11c in the development of atherosclerosis and in monocyte adhesion and recruitment into atherosclerotic lesions by using animal models of obesity with hypercholesterolemia, and by in vitro flow adhesion assay and in vivo adoptive transfer of blood monocytes with or without CD11c;and Aim 3. Examine the role of CD11c in AT inflammation including macrophage and T cell accumulation and activation;and in metabolic abnormalities in mice with HF diet-induced obesity. This approach will help us better understand the mechanisms of obesity- linked inflammation, specifically the role of CD11c in recruitment and activation of macrophages and T cells in atherosclerotic lesions and AT. Considering the demonstrated role of chronic inflammation in obesity-related CVD and metabolic disease, this approach is of significant interest and has the potential to provide novel preventive and therapeutic targets for obesity-linked diseases. PUBLIC HEALTH RELEVANCE: Obesity is associated with inflammation, which contributes to the development of atherosclerosis and diabetes. Our project will study the role of CD11c, a "sticky" protein on white blood cells, in inflammation, including its contribution to the development of atherosclerosis and diabetes associated with obesity. This study has the potential to provide novel preventive and therapeutic targets for obesity-related atherosclerosis and diabetes.
Funding Period: 2010-04-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity
    Qun Wang
    Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, Texas, USA
    Obesity (Silver Spring) 19:505-13. 2011
  2. pmc CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to vascular cell adhesion molecule-1
    R Michael Gower
    Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
    Arterioscler Thromb Vasc Biol 31:160-6. 2011
  3. pmc Differential effect of weight loss with low-fat diet or high-fat diet restriction on inflammation in the liver and adipose tissue of mice with diet-induced obesity
    Qun Wang
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin, M S A 601, Houston, TX 77030, USA
    Atherosclerosis 219:100-8. 2011
  4. pmc ApoE and the role of very low density lipoproteins in adipose tissue inflammation
    Jiali Wang
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin, M S A 601, Houston, TX 77030, USA
    Atherosclerosis 223:342-9. 2012
  5. pmc On-chip phenotypic analysis of inflammatory monocytes in atherogenesis and myocardial infarction
    Greg A Foster
    Department of Biomedical Engineering, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 110:13944-9. 2013
  6. pmc Attenuated adipose tissue and skeletal muscle inflammation in obese mice with combined CD4+ and CD8+ T cell deficiency
    Ilvira M Khan
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
    Atherosclerosis 233:419-28. 2014

Detail Information

Publications6

  1. pmc Effect of the cannabinoid receptor-1 antagonist rimonabant on inflammation in mice with diet-induced obesity
    Qun Wang
    Department of Medicine, Section of Cardiovascular Research, Baylor College of Medicine, Houston, Texas, USA
    Obesity (Silver Spring) 19:505-13. 2011
    ..Thus, rimonabant induced weight loss in obese mice by diet-intake-dependent and -independent fashions. Rimonabant decreased inflammation in obese mice, possibly through a primary effect on weight reduction...
  2. pmc CD11c/CD18 expression is upregulated on blood monocytes during hypertriglyceridemia and enhances adhesion to vascular cell adhesion molecule-1
    R Michael Gower
    Department of Biomedical Engineering, University of California, Davis, CA 95616, USA
    Arterioscler Thromb Vasc Biol 31:160-6. 2011
    ..Involvement of β(2)-integrin CD11c/CD18 in atherogenesis was recently shown in dyslipidemic mice, which motivates our study of its inflammatory function during hypertriglyceridemia in humans...
  3. pmc Differential effect of weight loss with low-fat diet or high-fat diet restriction on inflammation in the liver and adipose tissue of mice with diet-induced obesity
    Qun Wang
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin, M S A 601, Houston, TX 77030, USA
    Atherosclerosis 219:100-8. 2011
    ..We studied the effects of weight loss induced by either a low-fat normal diet (ND) or restriction of high-fat diet (HFD) on hepatic steatosis, inflammation in the liver and adipose tissue (AT), and blood monocytes of obese mice...
  4. pmc ApoE and the role of very low density lipoproteins in adipose tissue inflammation
    Jiali Wang
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, 6565 Fannin, M S A 601, Houston, TX 77030, USA
    Atherosclerosis 223:342-9. 2012
    ..To identify the role of triglyceride-rich lipoproteins (TGRLs) and apoE, a major apolipoprotein in TGRLs, in adipose tissue inflammation with high-fat diet (HFD)-induced obesity...
  5. pmc On-chip phenotypic analysis of inflammatory monocytes in atherogenesis and myocardial infarction
    Greg A Foster
    Department of Biomedical Engineering, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
    Proc Natl Acad Sci U S A 110:13944-9. 2013
    ..These experiments reveal that CD11c/CD18 is an inducible integrin whose expression correlates with a monocyte inflammatory state in subjects at risk for atherogenesis and in patients with myocardial infarction. ..
  6. pmc Attenuated adipose tissue and skeletal muscle inflammation in obese mice with combined CD4+ and CD8+ T cell deficiency
    Ilvira M Khan
    Division of Atherosclerosis and Vascular Medicine, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, USA Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
    Atherosclerosis 233:419-28. 2014
    ..Furthermore, we investigated whether CD4+IFNγ+ (TH1) cells are involved in skeletal muscle and adipose tissue metabolic dysfunction that accompanies obesity...

Research Grants30

  1. Role of the Interleukin12/STAT4 Pathway in Insulin Resistance and Atherosclerosis
    Jerry L Nadler; Fiscal Year: 2013
    ..The completed project should identify an innovative therapeutic target that could lead to new treatment to reduce atherosclerosis associated with central obesity insulin resistance and diabetes. ..
  2. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  3. Sparstolonin B as an anti-atherogenic agent
    Daping Fan; Fiscal Year: 2013
    ..The confirmation of the hypothesis will usher the development of SsnB as a new anti-atherogenic agent;it will also provide a pharmacological evidence for the causal role of TLR2 and TLR4 signaling in atherogenesis. ..
  4. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  5. Vascular mimetics to study inflammation and atherosclerosis
    SCOTT IRWIN SIMON; Fiscal Year: 2013
    ....
  6. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..