Transcriptional Control of Macrophage in Atherogenesis

Summary

Principal Investigator: Ajay Chawla
Abstract: DESCRIPTION (provided by applicant): Our long-term goal is to understand how nuclear receptors regulate monocyte and macrophage gene expression in the context of chronic metabolic diseases, such as atherosclerosis and obesity-induced insulin resistance. Recent studies indicate that classical activation of resident macrophages by Th1-type stimuli, such as interferon gamma, plays a key pathogenic role in both atherosclerosis and obesity-induced insulin resistance. In contrast, Th2 cytokines interleukin-4 and -13 (IL-4 and IL-13) promote alternative activation of tissue macrophages to ameliorate metabolic syndrome. Notably, we have reported that the maturation of alternatively activated macrophages in tissues is absolutely dependent on the transcriptional activity of Peroxisome Proliferator Activated Receptors gamma and delta (PPAR gamma and delta), providing a mechanistic basis for the protective functions of these receptors in obesity-induced insulin resistance and atherosclerosis. In addition to their well-established functions in macrophage biology, we recently discovered that PPAR gamma and delta are also expressed in circulating mouse monocytes, the precursors of recruited and resident tissue macrophages. Moreover, PPAR gamma and delta are transcriptionally competent in monocytic cells, suggesting that these receptors might also coordinate gene expression networks in these cells. Therefore, studies proposed in the present grant application will take molecular, cellular, and genetic approaches, including monocyte- and macrophage-specific knockouts, to further investigate how PPAR gamma and delta control the maturation of monocytes and activation of macrophages in lean and obese mice. Data from these studies will greatly enhance the molecular understanding of how PPAR gamma and delta regulate monocyte and macrophage functions under physiologic and pathophysiologic conditions, leading to better utilization of their ligands for the treatment of metabolic complications of obesity, such as atherosclerosis. The specific aims of this proposal are to: 1) Develop and validate a novel cell culture system for adoptive transfer of monocytic cells, 2) Investigate the regulatory roles of PPAR gamma and delta in monocyte biology in both mice and humans, and 3) Investigate the functions of PPARs development of advanced necrotic plaques.
Funding Period: 2004-04-01 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation
    Divya Vats
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine and Graduate Program in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA
    Cell Metab 4:13-24. 2006
  2. pmc Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice
    Lily C Chao
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
    J Lipid Res 54:806-15. 2013
  3. pmc Dysfunction of inflammation-resolving pathways is associated with exaggerated postoperative cognitive decline in a rat model of the metabolic syndrome
    Xiao Su
    Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, United States of America
    Mol Med 18:1481-90. 2012
  4. pmc Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis
    Justin I Odegaard
    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158 9001, USA
    Science 339:172-7. 2013
  5. pmc Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages
    Ari B Molofsky
    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco 94143, USA
    J Exp Med 210:535-49. 2013
  6. pmc The immune system as a sensor of the metabolic state
    Justin I Odegaard
    Cardiovascular Research Institute, University of California San Francisco, CA 94158 9001, USA
    Immunity 38:644-54. 2013
  7. pmc Macrophage biology in development, homeostasis and disease
    Thomas A Wynn
    Immunopathogenesis Section, Program in Tissue Immunity and Repair and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20877 8003, USA
    Nature 496:445-55. 2013
  8. pmc Salmonella require the fatty acid regulator PPARδ for the establishment of a metabolic environment essential for long-term persistence
    Nicholas A Eisele
    Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cell Host Microbe 14:171-82. 2013
  9. pmc Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes
    Khoa D Nguyen
    Cardiovascular Research Institute, University of California, San Francisco, CA 94158 9001, USA
    Science 341:1483-8. 2013
  10. pmc Blood spotlight on leukocytes and obesity
    José Barreto Campello Carvalheira
    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA
    Blood 122:3263-7. 2013

Detail Information

Publications29

  1. pmc Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation
    Divya Vats
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine and Graduate Program in Immunology, Stanford University School of Medicine, Stanford, California 94305, USA
    Cell Metab 4:13-24. 2006
    ....
  2. pmc Bone marrow NR4A expression is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice
    Lily C Chao
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
    J Lipid Res 54:806-15. 2013
    ..Collectively, our results suggest that alterations in the Ly6C(lo) monocyte population and bone marrow NR4A expression do not play dominant roles in macrophage polarization or the development of atherosclerosis in mice...
  3. pmc Dysfunction of inflammation-resolving pathways is associated with exaggerated postoperative cognitive decline in a rat model of the metabolic syndrome
    Xiao Su
    Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, United States of America
    Mol Med 18:1481-90. 2012
    ..Rats with the metabolic syndrome have ineffective inflammation-resolving mechanisms that represent plausible reasons for the exaggerated and persistent PCD...
  4. pmc Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis
    Justin I Odegaard
    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158 9001, USA
    Science 339:172-7. 2013
    ..An appreciation of the adaptive context in which these responses arose is useful for understanding their pathogenic actions in disease...
  5. pmc Innate lymphoid type 2 cells sustain visceral adipose tissue eosinophils and alternatively activated macrophages
    Ari B Molofsky
    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco 94143, USA
    J Exp Med 210:535-49. 2013
    ..Thus, ILC2s are resident in VAT and promote eosinophils and AAM implicated in metabolic homeostasis, and this axis is enhanced during Th2-associated immune stimulation...
  6. pmc The immune system as a sensor of the metabolic state
    Justin I Odegaard
    Cardiovascular Research Institute, University of California San Francisco, CA 94158 9001, USA
    Immunity 38:644-54. 2013
    ..Such an integrated perspective both advances our understanding of basic physiology and highlights potential opportunities for therapeutic intervention in metabolic dysfunction...
  7. pmc Macrophage biology in development, homeostasis and disease
    Thomas A Wynn
    Immunopathogenesis Section, Program in Tissue Immunity and Repair and Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20877 8003, USA
    Nature 496:445-55. 2013
    ..It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases...
  8. pmc Salmonella require the fatty acid regulator PPARδ for the establishment of a metabolic environment essential for long-term persistence
    Nicholas A Eisele
    Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
    Cell Host Microbe 14:171-82. 2013
    ..These data suggest that M2 macrophages represent a unique niche for long-term intracellular bacterial survival and link the PPARδ-regulated metabolic state of the host cell to persistent bacterial infection. ..
  9. pmc Circadian gene Bmal1 regulates diurnal oscillations of Ly6C(hi) inflammatory monocytes
    Khoa D Nguyen
    Cardiovascular Research Institute, University of California, San Francisco, CA 94158 9001, USA
    Science 341:1483-8. 2013
    ..These findings have unveiled a critical role for BMAL1 in controlling the diurnal rhythms in Ly6C(hi) monocyte numbers. ..
  10. pmc Blood spotlight on leukocytes and obesity
    José Barreto Campello Carvalheira
    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA
    Blood 122:3263-7. 2013
    ..In this review, we discuss the roles of visceral adipose tissue's salient leukocyte lineages in the transition to obesity and highlight key points at which this emerging immune axis may be manipulated for therapeutic effect. ..
  11. pmc Adipose tissue macrophages: Amicus adipem?
    Justin I Odegaard
    Cardiovascular Research Institute, University of California, San Francisco, 94158 9001, USA
    Cell Metab 18:767-8. 2013
    ..Xu et al. (2013) now describe the unexpected ability of adipose tissue macrophages to buffer lipids released from obese adipocytes in a manner independent of inflammatory macrophage activation. ..
  12. ncbi Metabolic regulation of immune responses
    Kirthana Ganeshan
    Cardiovascular Research Institute
    Annu Rev Immunol 32:609-34. 2014
    ..A better understanding of the metabolic checkpoints that control these transitions might provide new insights for modulating immunity in infection, cancer, or inflammatory disorders. ..
  13. pmc Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin
    Jan Mauer
    1 Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, Cologne, Germany 2 Max Planck Institute for Neurological Research, Cologne, Germany 3 Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Cologne, Germany 4
    Nat Immunol 15:423-30. 2014
    ..Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation. ..
  14. pmc Connecting type 1 and type 2 diabetes through innate immunity
    Justin I Odegaard
    Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
    Cold Spring Harb Perspect Med 2:a007724. 2012
    ..We conclude with a discussion of the therapeutic implications of this integrated understanding of diabetic pathology...
  15. pmc Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis
    Khoa D Nguyen
    Immunology Program, Stanford University, Palo Alto, California 94305, USA
    Nature 480:104-8. 2011
    ..Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold...
  16. pmc Macrophage-mediated inflammation in metabolic disease
    Ajay Chawla
    Cardiovascular Research Institute, University of California San Francisco, California 94158 9001, USA
    Nat Rev Immunol 11:738-49. 2011
    ..In particular, we focus our discussion on the pathogenic and protective functions of classically and alternatively activated macrophages, respectively, in experimental models of obesity and metabolic disease...
  17. pmc Quantitative expansion of ES cell-derived myeloid progenitors capable of differentiating into macrophages
    Justin I Odegaard
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine and Graduate Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305 5103, USA
    J Leukoc Biol 81:711-9. 2007
    ....
  18. pmc Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance
    Justin I Odegaard
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, California 94305 5103, USA
    Nature 447:1116-20. 2007
    ....
  19. pmc Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance
    Justin I Odegaard
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 5103, USA
    Cell Metab 7:496-507. 2008
    ..Taken together, these data suggest an unexpected beneficial role for alternatively activated Kupffer cells in metabolic syndrome and type 2 diabetes...
  20. pmc Mechanisms of macrophage activation in obesity-induced insulin resistance
    Justin I Odegaard
    Graduate Program in Immunology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 5103, USA
    Nat Clin Pract Endocrinol Metab 4:619-26. 2008
    ..The functional importance of macrophage activation is further discussed in the context of host defense to highlight the crosstalk between innate immunity and metabolism...
  21. pmc PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance
    Lata Mukundan
    Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
    Nat Med 15:1266-72. 2009
    ..Thus, PPAR-delta has a pivotal role in orchestrating the timely disposal of apoptotic cells by macrophages, ensuring that tolerance to self is maintained...
  22. pmc Control of macrophage activation and function by PPARs
    Ajay Chawla
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 5103, USA
    Circ Res 106:1559-69. 2010
    ....
  23. pmc Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity
    Shannon E Dunn
    Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
    J Exp Med 207:1599-608. 2010
    ..Collectively, these findings suggest that PPAR-delta serves as an important molecular brake for the control of autoimmune inflammation...
  24. pmc In obesity and weight loss, all roads lead to the mighty macrophage
    Alex Red Eagle
    Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
    J Clin Invest 120:3437-40. 2010
    ..In this issue of the JCI, Kosteli and colleagues demonstrate that weight loss is unexpectedly also associated with rapid, albeit transient, recruitment of macrophages to WAT and that this appears to be related to lipolysis...
  25. pmc Alternative macrophage activation and metabolism
    Justin I Odegaard
    Department of Pathology, Stanford University School of Medicine, California 94305 5103, USA
    Annu Rev Pathol 6:275-97. 2011
    ..The therapeutic implications of this conclusion are profound because they suggest that pharmacologic targeting of macrophage activation, rather than simply inflammation, might be efficacious in treating this global epidemic...
  26. pmc IL-4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity
    Roberto R Ricardo-Gonzalez
    Division of Endocrinology, Metabolism and Gerontology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 107:22617-22. 2010
    ....
  27. pmc Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis
    DAVINA WU
    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143 0795, USA
    Science 332:243-7. 2011
    ..Our results suggest that eosinophils play an unexpected role in metabolic homeostasis through maintenance of adipose AAMs...
  28. pmc Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation
    Krisztina Köröskényi
    Department of Biochemistry and Molecular Biology, Signaling and Apoptosis Research Group, Hungarian Academy of Sciences, Research Center of Molecular Medicine, University of Debrecen, Debrecen H 4012, Hungary
    J Immunol 186:7144-55. 2011
    ..Altogether, our data indicate that adenosine is one of the soluble mediators released by macrophages that mediate engulfment-dependent apoptotic cell suppression of inflammation...
  29. pmc Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat
    Yifu Qiu
    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158 9001, USA
    Cell 157:1292-308. 2014
    ..Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity. ..

Research Grants30

  1. Adiponectin Actions on the Monocyte to Reduce Atherosclerosis
    Rajendra K Tangirala; Fiscal Year: 2013
    ..abstract_text> ..
  2. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  3. Improving Cardiac Function After Myocardial Infarction
    Steven R Houser; Fiscal Year: 2013
    ..A gene vector core will generate AAV6 vectors with novel therapeutics for testing in the pig Ml model. An administrative core will ensure data sharing and effective use of all resources. ..
  4. Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma
    Yihong Wan; Fiscal Year: 2013
    ..Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. ..
  5. The anti-inflammatory mRNA-binding protein ZFP36 in Obesity and Metabolism
    CALEB BENJAMIN KALLEN; Fiscal Year: 2013
    ..Our work may identify ZFP36 as a new therapeutic target for important medical conditions exacerbated by obesity and inflammation including atherosclerosis and diabetes. ..
  6. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  7. KLF4-Dependent Regulation of SMC Differentiation and Phenotypic Switching
    Gary K Owens; Fiscal Year: 2013
    ..abstract_text> ..
  8. Toll-Like Receptors and Atherosclerosis in Diabetes
    Yan Huang; Fiscal Year: 2013
    ..Overall, this research project will establish a rationale for targeting TLR4 in treatment of atherosclerosis in diabetic patients. Thus, this study is highly relevant to Veterans'health. ..
  9. A Novel Cellular Mechanism for Reducing Hyperlipidemia
    Jingwen Liu; Fiscal Year: 2013
    ....
  10. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  11. Monocyte activation and the role of CD11c in obesity-linked metabolic syndrome
    Huaizhu Wu; Fiscal Year: 2013
    ..This study has the potential to provide novel preventive and therapeutic targets for obesity-related atherosclerosis and diabetes. ..
  12. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  13. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  14. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  15. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  16. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  17. Role of IgE in Atherosclerosis
    Guo Ping Shi; Fiscal Year: 2013
    ..We anticipate that the experiments proposed in both aims will establish an important and novel role of IgE in M[unreadable] and vascular cell pathobiology, and a direct participation of IgE in atherogenesis. ..
  18. Nuclear receptor mechanisms controlling macrophage function in health and disease
    Ajay Chawla; Fiscal Year: 2013
    ..Insights from these studies should lead to development of new therapeutics to treat chronic inflammatory and degenerative diseases, and improve modalities for tissue regeneration. ..
  19. 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. ..