Role of natural indoles in experimental autoimmune encephalomyelitis

Summary

Principal Investigator: Mitzi Nagarkatti
Abstract: DESCRIPTION (provided by applicant): There are over 80 different autoimmune diseases that are debilitating against which currently there is no cure. Thus, patients resort to complementary and alternative medicine (CAM) to find relief from pain and inflammation. Multiple Sclerosis (MS) is one such autoimmune disease that affects ~350,000-500,000 people in the US. It is a chronic disease characterized by inflammation in the central nervous system that results in neuron demyelination leading to paralysis. Dietary indoles including indole-3-carbinol (I3C) found in cruciferous vegetables such as cauliflower, cabbage and Brussels sprouts, as well as its derivative, diindolylmethane (DIM) have also been known for their health benefits and for their anti-cancer properties. Interestingly, these compounds can bind to the aryl hydrocarbon receptor (AhR), which is well characterized as a transcription factor that regulates xenobiotic metabolism. Also, recent studies suggested that AhR may also regulate certain important immune functions such as T cell differentiation. We have made an exciting observation that dietary indoles such as DIM can completely suppress the clinical disease in an experimental model of MS known as Experimental Autoimmune Encephalomyelitis (EAE). In the current study, we will test the central hypothesis that treatment with these naturally- occurring indoles is effective against induction and progression of EAE through a central pathway of activation of AhR, leading to suppression of proinflammatory Th1/Th17cells and induction of T regs/Th2 cells via epigenetic regulatory mechanisms such as DNA methylation and miRNA dysregulation that block neuroinflammation. To this end, we will test the following aims: In aim 1, we will examine whether treatment with indoles such as I3C or DIM leads to decreased neuroinflammation by downregulation of Th1 and Th17 cell responses against myelin antigens and upregulation of Th2 and FoxP3+ Tregs. We will test whether activation of AhR by these indoles leads to dysregulation in the Th/Treg cell responses using AhR knock out (KO) mice. In aim 2, we will test the central hypothesis that indoles facilitate Th17 to Treg switch in EAE mice by DNA hypomethylation of Foxp3 gene promoter while silencing the Th17 activity by hypermethylation of IL-17 promoters. Lastly, in aim 3, we will test the hypothesis that administration of these indoles triggers dysregulation in the expression of microRNA-466i and microRNA-325 that leads to increased polarization of Tregs and decreased differentiation of T17 cells. The current study investigates the mechanism of action of plant-derived indoles used as dietary supplements, specifically addressing the role of AhR activation in the regulation of inflammation. These studies should provide novel insights into the basic mechanisms through which plant indoles exhibit anti- inflammatory properties so that they can be used against a wide range of autoimmune and inflammatory diseases.
Funding Period: 2011-08-01 - 2016-07-31
more information: NIH RePORT

Top Publications

  1. pmc Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis
    Udai P Singh
    Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
    Toxicol Appl Pharmacol 258:256-67. 2012
  2. pmc 3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways
    Michael Rouse
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina
    J Pharmacol Exp Ther 350:341-52. 2014
  3. pmc Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction
    Austin R Jackson
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America
    PLoS ONE 9:e93954. 2014
  4. pmc Characterization of endocannabinoid-mediated induction of myeloid-derived suppressor cells involving mast cells and MCP-1
    Austin R Jackson
    1 Microbiology and Immunology, University of South Carolina School of Medicine, 6439 Garner s Ferry Rd, Columbia, SC 29208, USA
    J Leukoc Biol 95:609-19. 2014
  5. ncbi Role of cytokines as a double-edged sword in sepsis
    HINA CHAUDHRY
    Institute for Tumor Immunology, Ludong University School of Life Sciences, 186 Hongqi Middle Road, Yantai, Shandong 264025, PR China
    In Vivo 27:669-84. 2013
  6. pmc Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Δ9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein α by microRNA-690
    Venkatesh L Hegde
    From the Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208
    J Biol Chem 288:36810-26. 2013
  7. pmc Natural indoles, indole-3-carbinol and 3,3'-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression
    Philip B Busbee
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
    Toxicol Appl Pharmacol 274:7-16. 2014
  8. pmc Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders
    Philip B Busbee
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USA
    Nutr Rev 71:353-69. 2013
  9. pmc Indoles mitigate the development of experimental autoimmune encephalomyelitis by induction of reciprocal differentiation of regulatory T cells and Th17 cells
    Michael Rouse
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
    Br J Pharmacol 169:1305-21. 2013
  10. pmc MicroRNA let-7e is associated with the pathogenesis of experimental autoimmune encephalomyelitis
    Hongbing Guan
    Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
    Eur J Immunol 43:104-14. 2013

Detail Information

Publications14

  1. pmc Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis
    Udai P Singh
    Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
    Toxicol Appl Pharmacol 258:256-67. 2012
    ..These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD...
  2. pmc 3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways
    Michael Rouse
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina
    J Pharmacol Exp Ther 350:341-52. 2014
    ....
  3. pmc Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction
    Austin R Jackson
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America
    PLoS ONE 9:e93954. 2014
    ..Together, the current study demonstrates that AEA may suppress Th-17 cell-mediated DTH response by inducing IL-10 which in turn triggers miRNA that target proinflammatory pathways. ..
  4. pmc Characterization of endocannabinoid-mediated induction of myeloid-derived suppressor cells involving mast cells and MCP-1
    Austin R Jackson
    1 Microbiology and Immunology, University of South Carolina School of Medicine, 6439 Garner s Ferry Rd, Columbia, SC 29208, USA
    J Leukoc Biol 95:609-19. 2014
    ..Our studies demonstrate for the first time that endocannaboinids activate CB1 on mast cells to induce MCP-1, which facilitates recruitment of monocytic MDSCs. ..
  5. ncbi Role of cytokines as a double-edged sword in sepsis
    HINA CHAUDHRY
    Institute for Tumor Immunology, Ludong University School of Life Sciences, 186 Hongqi Middle Road, Yantai, Shandong 264025, PR China
    In Vivo 27:669-84. 2013
    ..Sepsis is a deadly immunological disorder and its pathophysiology is still poorly understood. We aimed to determine if specific pro-inflammatory and anti-inflammatory cytokines can be used as diagnostic and therapeutic targets for sepsis...
  6. pmc Distinct microRNA expression profile and targeted biological pathways in functional myeloid-derived suppressor cells induced by Δ9-tetrahydrocannabinol in vivo: regulation of CCAAT/enhancer-binding protein α by microRNA-690
    Venkatesh L Hegde
    From the Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208
    J Biol Chem 288:36810-26. 2013
    ..Select miRNA such as miR-690 targeting genes involved in myeloid expansion and differentiation likely play crucial roles in this process and therefore in cannabinoid-induced immunosuppression. ..
  7. pmc Natural indoles, indole-3-carbinol and 3,3'-diindolymethane, inhibit T cell activation by staphylococcal enterotoxin B through epigenetic regulation involving HDAC expression
    Philip B Busbee
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
    Toxicol Appl Pharmacol 274:7-16. 2014
    ..These studies not only suggest for the first time that plant-derived indoles are potent suppressors of SEB-induced T cell activation and cytokine storm but also that they may mediate these effects by acting as HDAC inhibitors. ..
  8. pmc Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders
    Philip B Busbee
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina 29208, USA
    Nutr Rev 71:353-69. 2013
    ..As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases...
  9. pmc Indoles mitigate the development of experimental autoimmune encephalomyelitis by induction of reciprocal differentiation of regulatory T cells and Th17 cells
    Michael Rouse
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
    Br J Pharmacol 169:1305-21. 2013
    ....
  10. pmc MicroRNA let-7e is associated with the pathogenesis of experimental autoimmune encephalomyelitis
    Hongbing Guan
    Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209, USA
    Eur J Immunol 43:104-14. 2013
    ..We also identified IL-10 as one of the functional targets of let-7e. Together, we propose that let-7e is a new miRNA involved in the regulation of encephalitogenic T-cell differentiation and the pathogenesis of EAE...
  11. pmc Prenatal exposure to TCDD triggers significant modulation of microRNA expression profile in the thymus that affects consequent gene expression
    Narendra P Singh
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina, United States of America
    PLoS ONE 7:e45054. 2012
    ....
  12. pmc The role of IL-2 in the activation and expansion of regulatory T-cells and the development of experimental autoimmune encephalomyelitis
    Michael Rouse
    Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
    Immunobiology 218:674-82. 2013
    ....
  13. pmc Prenatal exposure of mice to diethylstilbestrol disrupts T-cell differentiation by regulating Fas/Fas ligand expression through estrogen receptor element and nuclear factor-κB motifs
    Narendra P Singh
    Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
    J Pharmacol Exp Ther 343:351-61. 2012
    ....
  14. pmc Expression, regulation and function of microRNAs in multiple sclerosis
    Xinting Ma
    1 Institute for Tumor Immunology, Ludong University College of Life Sciences, 186 Hongqi Middle Road, Yantai, Shandong 264025, China
    Int J Med Sci 11:810-8. 2014
    ..The dysregulated miRNAs such as miR-155 and miR-326 may be used as diagnostic markers and therapeutic targets for MS. ..

Research Grants62

  1. Immunobiology and Pathogenesis of Pulmonary Tularemia (Metzger, PD)
    Dennis W Metzger; Fiscal Year: 2013
    ....
  2. INNATE IMMUNE RESPONSE TO MICROBIAL INFECTION
    William M Nauseef; Fiscal Year: 2013
    ....
  3. Neurodevelopment and Improving Children's Health following EtS exposure (NICHES)
    Susan Kay Murphy; Fiscal Year: 2013
    ....
  4. Disease chronicity in juvenile dermatomyositis (JDM): Epigenetic clues
    Lauren M Pachman; Fiscal Year: 2013
    ..The goal is to identify specific markers, like microRNA, or "turned on genes" that may be key to repair the vascular damage and to identify more effective medical interventions. ..
  5. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
    ..Core C ("Gene Targeting Core";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice. ..
  6. Serotonin as a Regulator of Bone Mass Accrual: Basic and Clinical
    Gerard Karsenty; Fiscal Year: 2013
    ..Together our studies should provide important and novel insights in the genetic and molecular control of bone remodeling as well as in the pathogenesis and treatment of osteoporosis, a major disease of aging. ..
  7. Interferons as adjuvants for tolerogenic vaccines
    Mark D Mannie; Fiscal Year: 2013
    ....
  8. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
    ..abstract_text> ..
  9. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  10. The role of the innate immune system on Treg reprogramming in human autoimmune di
    Kevan C Herold; Fiscal Year: 2013
    ..In addition, these studies may identify pathways that may be targeted by existing or novel immune therapeutics. ..
  11. Viral suppression of CNS autoimmunity
    Stephen A Stohlman; Fiscal Year: 2013
    ..However, as part of the inflammation which controls virus, a suppressive anti- inflammatory environment is established in the central nervous system which prevents autoimmunity. ..
  12. Research Center for Pharmacology &Drug Toxicology
    L Jackson Roberts; Fiscal Year: 2013
    ....
  13. Role of Eicosanoids in Renal Function
    NANCY JOAN BROWN; Fiscal Year: 2013
    ..These are needed for the development of meaningful approaches for: a) the unequivocal definition of human pathophysiological significance, and b) future pharmacological targeting, and clinical diagnosis and intervention. ..
  14. Primary Immune Deficiency Treatment Consortium
    Morton Cowan; Fiscal Year: 2013
    ..These studies will resolve critical questions concerning HCT for these disorders and form the basis for future prospective clinical trials. ..
  15. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
    ..Finally, and central to this PPG, our results will greatly enhance our ability to design better and safer BCDT therapies and to develop biomarkers of B cell targeted treatments efficacy and safety. ..
  16. Regulatory monocytes in CNS autoimmune disease
    Scott S Zamvil; Fiscal Year: 2013
    ..abstract_text> ..
  17. Immune Regulation of Neural Stem Cell Program In EAE
    Samia J Khoury; Fiscal Year: 2013
    ..These investigations will have an impact on our understanding of the pathogenesis of neuro-degeneration in multiple sclerosis and provide a model that may be used to target treatments for chronic disease. ..
  18. Molecular and Cellular Mechanisms of IL-17 Signaling
    Xiaoxia Li; Fiscal Year: 2013
    ....
  19. Regulatory T Cells in Malignant Glioma
    Maciej S Lesniak; Fiscal Year: 2013
    ..abstract_text> ..
  20. NIPBL, Cohesin and Related Structural Birth Defects
    Ian D Krantz; Fiscal Year: 2013
    ..This Program outlines a plan to characterize cohesin's function in gene regulation, identify its effector genes and evaluate their role in causing isolated birth defects of the types seen in CdLS. ..
  21. Coordinating Center of Excellence in Social Promotion of Health Equity Research
    GLORIA S MCCUTCHEON; Fiscal Year: 2013
    ..abstract_text> ..
  22. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  23. INITIATION OF HUMAN LABOR: PREVENTION OF PREMATURITY
    Carole R Mendelson; Fiscal Year: 2013
    ..We propose that these interrelated projects, carried out by a highly interactive research team, will achieve the long-range goals of this Program and contribute to a reduction in the incidence of preterm birth. ..
  24. Elucidating a role for a hematopoietic-tropic microRNA in autoreactive T cells
    Anthony T Vella; Fiscal Year: 2013
    ..Thus, this R21 proposal will explore how a new miRNA can impact specific T cell function, which may lead to a novel translational approach for multiple sclerosis in humans. ..
  25. International Comparisons of Well-Being, Health and Retirement
    ARIE KAPTEYN; Fiscal Year: 2013
    ..unreadable] Make harmonized institutional information available to the wider research community. ..
  26. Role of CD44 in experimental Multiple Sclerosis
    Mitzi Nagarkatti; Fiscal Year: 2013
    ..abstract_text> ..
  27. H1R Signaling and Immune Deviation in EAE
    Cory Teuscher; Fiscal Year: 2013
    ....
  28. Transcriptional Control of Autoimmunity in the Central Nervous System
    Howard L Weiner; Fiscal Year: 2013
    ..The core will service all projects. An Administrative Core will coordinate the various administrative aspects of the PPG and a Scientific Advisory Board has been assembled to provide scientific oversight. ..
  29. Neuropeptides and Regulatory T cells
    Doina Ganea; Fiscal Year: 2013
    ..The ultimate goal of the present proposal is the development of a combined therapy based on genetically modified tolerogenic dendritic cells, which represents a novel therapeutic approach for the treatment of autoimmune diseases. ..
  30. Negative Regulatory Mechanisms for Myelin Specific T cells
    Brian D Evavold; Fiscal Year: 2013
    ..Two specific aims are designed to test this hypothesis. Aim 1: To define SHP-1 regulation in myelin reactive T cells- Aim 2: To determine the efficacy of MVP and adoptive T cell therapy in regulating autoimmune disease- ..
  31. XT-101: A Potent IL-10 Based Therapy for Treating Multiple Sclerosis.
    Raymond A Chavez; Fiscal Year: 2013
    ..Because the method of action of XT-101 is markedly different from all existing or imminent MS treatments, it has the potential to be an extremely useful addition and complement to current medical practice. ..
  32. Innate Regulation and CD4+Th1/17 Immunity in TMEV-Induced Demyelination
    Stephen D Miller; Fiscal Year: 2013
    ....
  33. PAHs: New Technologies and Emerging Health Risks
    David E Williams; Fiscal Year: 2013
    ..Accomplishing these goals will provide significant scientific advancement and improve the quality of life for impacted communities. ..
  34. Sulfatide-reactive type II NKT cells: repertoire and function
    Vipin Kumar; Fiscal Year: 2013
    ....
  35. Role of Brain-Specific microRNAs in Suppression of Autoimmune Neuroinflammation
    Howard L Weiner; Fiscal Year: 2013
    ..1 ..
  36. Signaling functions of Peli family of E3 ubiquitin ligases
    Shao Cong Sun; Fiscal Year: 2013
    ....
  37. DEVELOPMENT OF NOVEL THERAPIES FOR NIDDM
    Christopher B Newgard; Fiscal Year: 2013
    ..abstract_text> ..
  38. Immunopathological basis of PTSD
    Prakash S Nagarkatti; Fiscal Year: 2013
    ....
  39. Functional Annotation of the Pancreatic Cancer Genome
    Steven D Leach; Fiscal Year: 2013
    ..Together, these studies will dramatically accelerate the functional annotation of the pancreatic cancer genome, setting the stage for future therapeutic applications. ..
  40. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013
    ..Such an integrated interdisciplinary approach is possible only through continued support of this PPG. ..
  41. Autoimmunity Center of Excellence (ACE) at Stanford
    CHARLES GARRISON FATHMAN; Fiscal Year: 2013
    ..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
  42. Treating EAE disease with Fc-Dimers
    David M Mosser; Fiscal Year: 2013
    ..The goal of these studies is to demonstrate (for the first time) that a therapeutic directed at reprogramming macrophages has the potential to treat autoimmune diseases. ..
  43. Immune Mechanisms That Control Ectromelia Virus Infection
    Luis J Sigal; Fiscal Year: 2013
    ..The results from this Project will provide a comprehensive picture of the innate response to a peripheral virus infection. ..
  44. Mechanisms of Biodefense By Toll-Like Receptors
    Genhong Cheng; Fiscal Year: 2013
    ..The goal of our research is to further elucidate the molecular mechanisms responsible for IFN mediated anti-inflammatory responses and discover novel therapeutic targets for treating different types of autoimmune diseases. ..
  45. Neuroprotection and Myelin Repair Mechanisms in Multiple Sclerosis
    Inderjit Singh; Fiscal Year: 2013
    ....