Nuclear receptor mechanisms controlling macrophage function in health and disease

Summary

Principal Investigator: Ajay Chawla
Abstract: Our long-term goal is to understand how nuclear receptors regulate macrophage gene expression in health and disease. Nuclear receptors are ligand-activated transcription factors that modulate reproduction, development, and general metabolism. Recent studies indicate that expression of nuclear receptor superfamily is dynamically modulated during macrophage activation, indicating that these receptors play a pivotal role in orchestrating macrophage transcriptional responses. Indeed, work from our laboratory and those of others has shown that Peroxisome Proliferator Activated Receptors (PPARs) play a key regulatory role in macrophage cholesterol and fatty acid metabolism, and has provided the mechanistic basis for the cardioprotective functions of PPARs in coronary artery disease. While the inflammatory and pathogenic functions of macrophages are well appreciated, their homeostatic functions in tissue repair and immune tolerance remain poorly understood. Our preliminary data indicate the nuclear receptors PPAR delta and gamma play a key role in orchestrating macrophage transcriptional programs necessary for debris clearance and tissue regeneration. Moreover, genetic deletion of these receptors in macrophages severely compromises these homeostatic responses, leading to autoimmunity or impaired tissue repair. Therefore, studies proposed in the present grant application will take molecular, cellular, and genetic approaches, including tissue-specific knockouts, to further investigate how PPAR gamma and delta orchestrate macrophage gene expression during injury and repair. Data from these studies will greatly enhance the molecular understanding of how macrophage functions are regulated under physiologic and pathophysiologic conditions, and should lead to identification of new therapeutic targets for treating autoimmunity and/or improving tissue regeneration after injury. The specific aims of this proposal are to: 1) Determine the molecular mechanisms by which macrophage-specific PPAR delta and gamma control tolerogenic responses, 2) Investigate the regulatory role of macrophage-specific PPAR delta and gamma in tissue regeneration and repair, and 3) Generate macrophage-specific PPAR delta/gamma double knockout mice to elucidate their non-redundant functions in macrophages. PUBLIC HEALTH RELEVANCE: Macrophages take residence in almost all organs of the body, where they guard against damage and perform tissue repairs. Studies in this grant application will explore the role of nuclear receptors in controlling these reparative programs of macrophages. Insights from these studies should lead to development of new therapeutics to treat chronic inflammatory and degenerative diseases, and improve modalities for tissue regeneration.
Funding Period: 2009-05-20 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. 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
  2. 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
  3. pmc Eosinophils secrete IL-4 to facilitate liver regeneration
    Y P Sharon Goh
    Department of Genetics and Pathology, Stanford University, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 110:9914-9. 2013
  4. 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
  5. pmc Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration
    Jose E Heredia
    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158 9001, USA
    Cell 153:376-88. 2013
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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

Research Grants

Detail Information

Publications19

  1. 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...
  2. 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. ..
  3. pmc Eosinophils secrete IL-4 to facilitate liver regeneration
    Y P Sharon Goh
    Department of Genetics and Pathology, Stanford University, Stanford, CA 94305, USA
    Proc Natl Acad Sci U S A 110:9914-9. 2013
    ..Instead, IL-4 exerts its proliferative actions via IL-4Rα in hepatocytes. Our findings thus provide a unique mechanism by which eosinophil-derived IL-4 stimulates hepatocyte proliferation in regenerating liver...
  4. 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...
  5. pmc Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration
    Jose E Heredia
    Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158 9001, USA
    Cell 153:376-88. 2013
    ..Surprisingly, type 2 cytokine signaling is also required in FAPs, but not in myeloid cells, for rapid clearance of necrotic debris, a process that is necessary for timely and complete regeneration of tissues...
  6. 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...
  7. 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...
  8. 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...
  9. 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...
  10. 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...
  11. 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...
  12. 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...
  13. 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
    ....
  14. 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...
  15. 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...
  16. 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...
  17. 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
    ....
  18. 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. ..

Research Grants30

  1. MECHANISMS OF AUTOIMMUNITY IN SLE
    David Stephen Pisetsky; Fiscal Year: 2013
    ..Successful completion of these experiments will provide new insights in the pathogenic role in SLE of nuclear molecules in the form of microparticles as well as provide new biomarkers and potential targets of therapy. ..
  2. Effects of miR-21 and miR-155 inhibition in SLE
    Marianthi Kiriakidou; Fiscal Year: 2013
    ..To our knowledge HITS-CLIP has not been previously performed in SLE and the combined results of HITS-CLIP and RNAseq will offer a panoramic view of all genes directly regulated by miRNAs in cells of the immune system in mouse lupus. ..
  3. Characterization of LC3-Associated Phagocytosis
    Jennifer Martinez; Fiscal Year: 2013
    ..Further understanding the mechanisms by which autophagy, or in this case, LAP, can be triggered will provide researchers with novel therapeutic targets to the treatment of cancer. ..
  4. Targeting TAM Receptors to Modulate Inflammation and Autoimmunity
    Philip L Cohen; Fiscal Year: 2013
    ..If these antibodies have such an effect on models of arthritis and lupus in mice, a parallel approach to human inflammatory illnesses may open up, with the possibility of controlling many autoimmune and inflammatory diseases. ..
  5. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  6. A critical role of TAM receptors in autoimmune nephritis
    Wenhai Shao; Fiscal Year: 2013
    ..Results from this study will extend our understanding of the mechanisms in which Mer and Axl regulate chronic inflammation and autoimmunity. Data may reveal potential therapeutic targets for lupus nephritis. ..
  7. Modulation of B cell tolerance checkpoints by distinct Ras/Erk Pathways
    Andre Limnander; Fiscal Year: 2013
    ....