Inflammation in the CNS causes a wide range of clinical disorders including Multiple Sclerosis (MS). During an MS attack, inflammation in the central nervous system (CNS) can produce partial or complete paralysis. There is, as yet, no cure for MS. In the current study, we will test the effect of resveratrol (RES; 3,5,4'-trihydroxystilbene) on experimental autoimmune encephalomyelitis (EAE), an animal model of MS primarily triggered by activation of CD4+ MBP reactive Th1 and Th17 cells. Our laboratory was the first one to demonstrate that treatment with RES can ameliorate EAE. Moreover, we made an exciting and unique discovery that RES triggers induction of a recently characterized immunoregulatory cell called myeloid derived suppressor cell (MDSC). Based on our preliminary studies, we will test the hypothesis that RES suppresses neuroinflammation during EAE through epigenetic regulation and microRNA (miR) induction leading to the generation and activation of MDSCs which suppress myelin-specific T cells. Furthermore, we will test if the MDSC induction results from the activation of aryl hydrocarbon receptor (AhR) and/or estrogen receptor (ER) by RES. Understanding the precise mechanisms underlying the effects of RES on immune response against myelin may offer effective strategies to prevent induction and progression of the disease in MS as well as neuroinflammation associated with a number of other disorders.
Aim 1 : We will test the central hypothesis that RES activates AhR/ER to induce granulocyte colony stimulating factor (G-CSF) and arginase 1 (Arg1), which trigger differentiation of MDSCs from hematopoietic progenitor cells and their activation respectively. We will investigate the role of AhR and ER in the induction of MDSCs. We will investigate the transcriptional regulation of G-CSF and arginase 1 (Arg1) involving dioxin responsive elements (DRE) or estrogen-responsive elements (ERE) found on the promoters of these genes.
Aim 2 : We will test the central hypothesis that RES triggers MDSCs through epigenetic regulation of genes involved in MDSC differentiation and functions. The role of DNA methylation as well as histone modification will be determined in RES-induced MDSC in EAE mice by assessing genome-wide methylation using MeDip- Seq and ChiP-Seq, and by determining locus-specific methylation status. The DNA methylation and histone marks in the specific gene promoters of CD11b and Gr-1 as well as arginase 1 and iNOS will be validated.
Aim 3 : We will test the central hypothesis that RES induces miRNA that target specific genes involved in MDSC differentiation and functions. We will identify the role of miR223 that is induced by RES in hematopoietic stem cell differentiation into MDSC. We will also test whether the downregulation of miR185 and miR340 leads to increased iNOS and arginase production respectively. Together, our studies should provide novel information on how RES suppresses neuroinflammation through the induction of MDSCs via epigenetic regulation.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
2P01AT003961-06A1
Application #
8739824
Study Section
Special Emphasis Panel (ZAT1)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of South Carolina at Columbia
Department
Type
DUNS #
City
Columbia
State
SC
Country
United States
Zip Code
29208
Zhou, Juhua; Chaudhry, Hina; Zhong, Yin et al. (2015) Dysregulation in microRNA expression in peripheral blood mononuclear cells of sepsis patients is associated with immunopathology. Cytokine 71:89-100
Sido, Jessica Margaret; Nagarkatti, Prakash S; Nagarkatti, Mitzi (2015) Role of Endocannabinoid Activation of Peripheral CB1 Receptors in the Regulation of Autoimmune Disease. Int Rev Immunol 34:403-14
Jackson, Austin R; Hegde, Venkatesh L; Nagarkatti, Prakash S et al. (2014) Characterization of endocannabinoid-mediated induction of myeloid-derived suppressor cells involving mast cells and MCP-1. J Leukoc Biol 95:609-19
Jackson, Austin R; Nagarkatti, Prakash; Nagarkatti, Mitzi (2014) Anandamide attenuates Th-17 cell-mediated delayed-type hypersensitivity response by triggering IL-10 production and consequent microRNA induction. PLoS One 9:e93954
Zhou, Juhua; Nagarkatti, Prakash; Zhong, Yin et al. (2014) Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder. PLoS One 9:e94075
Singh, Udai P; Singh, Narendra P; Guan, Hongbing et al. (2014) The emerging role of leptin antagonist as potential therapeutic option for inflammatory bowel disease. Int Rev Immunol 33:23-33
Yang, Xiaoming; Hegde, Venkatesh L; Rao, Roshni et al. (2014) Histone modifications are associated with ?9-tetrahydrocannabinol-mediated alterations in antigen-specific T cell responses. J Biol Chem 289:18707-18
Chakrabarti, Mrinmay; Haque, Azizul; Banik, Naren L et al. (2014) Estrogen receptor agonists for attenuation of neuroinflammation and neurodegeneration. Brain Res Bull 109:22-31
Rouse, Michael; Rao, Roshni; Nagarkatti, Mitzi et al. (2014) 3,3'-diindolylmethane ameliorates experimental autoimmune encephalomyelitis by promoting cell cycle arrest and apoptosis in activated T cells through microRNA signaling pathways. J Pharmacol Exp Ther 350:341-52
Rao, Roshni; Rieder, Sadiye Amcaoglu; Nagarkatti, Prakash et al. (2014) Staphylococcal enterotoxin B-induced microRNA-155 targets SOCS1 to promote acute inflammatory lung injury. Infect Immun 82:2971-9

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