Multiple sclerosis (MS) is a neurodegenerative autoimmune disease that affects approximately one million people worldwide. There are over 28,000 veterans currently diagnosed with MS. Due to its high prevalence, in 2003, the Veterans Health Administration (VHA) established the MS Centers of Excellence which are committed to serving the health care needs of veterans with MS. There is increased prevalence of symptoms among recent Gulf war and other war veterans which include cognitive dysfunction, depression, chronic fatigue, musculoskeletal complaints, post-traumatic stress disorder and respiratory illness. According to recent testimony by the National Multiple Sclerosis Society (NMSS) to the Subcommittee on Defense, the increasing number of Gulf war veterans exhibiting symptoms described above may actually be suffering from multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is an animal model that recapitulates many features of MS in which Th1 and Th17 cells reactive against myelin antigens, cross the blood-brain barrier (BBB), enter the CNS and trigger inflammation, thereby causing demyelination and induction of paralysis. Studies from our laboratory have demonstrated that naove T cells express the standard form of CD44 (CD44s) and upon activation, express certain unique variant isoforms of CD44 (CD44v) through alternative splicing. Specifically, we have shown that CD44 isoforms such as CD44v6/v7 play a critical role in the interaction between activated T cells and endothelial cells (ECs) at sites of inflammation leading to EC injury. Interestingly, we have also noted that CD44 knockout (KO) mice exhibit increased resistance to EAE and decreased neuroinflammation when compared to CD44 wild type (WT) mice. Also, CD44 deficiency on T cells promoted a switch from Th1/Th17 to Th2/Treg differentiation. Preliminary studies also identified unique differences in miRNA expression profiles between CD44 WT and CD44 KO T cells. Based on the above studies, we will test the central hypothesis that naove T cells expressing CD44s, upon activation with myelin antigens presented by the DCs, undergo epigenetic modulation dysregulation in microRNA expression that regulate the transcription of inflammatory cytokine genes leading to promotion of Th1/Th17 differentiation. Furthermore, MOG-reactive T cells express unique CD44v isoforms which promote their interactions with ECs at the BBB via specific ligands, such as hyaluronic acid (HA) and/or osteopontin (OPN). Such an interaction would trigger EC injury and significant damage to the BBB. These events together promote inflammation and demyelination in the CNS. To this end, in the current study, we will identify CD44 variant isoforms expressed on activated MOG- specific T cells and study their role in the pathogenesis of EAE. Next, we will determine how interactions between CD44 with HA or OPN trigger epigenetic regulation by transcription factor gene promoter methylation and/or expression of miRs that lead to a switch in T differentiation from Th1/T17 cells to Th2/Tregs. Pharmacological and genetic intervention will be attempted for reversal of the Th/Treg functions and its effects on EAE. In addition, the interactions between CD44 expressed on antigen-specific T cells and specific ligands on BBB ECs leading to breakdown of BBB and trans-EC migration of T cells into CNS, during EAE, will be tested. Lastly, we will determine if targeting CD44s or CD44v, using strategies that include mimetics, would prevent the development and progression of EAE. Together, our studies should shed new light in understanding the role of CD44 isoforms in the regulation of MS and other inflammatory diseases of the CNS that affect a large proportion of Veterans as well provide novel treatment modalities that would benefit Veterans'health.

Public Health Relevance

Multiple Sclerosis (MS) is a debilitating autoimmune disease that affects ~350,000-500,000 people in the US. In this disease, the immune system attacks the brain cells and destroys them thereby causing paralysis and disability. Currently, there are over 28,000 veterans diagnosed with MS. War Veterans commonly suffer from post-traumatic disorders and other neurological disabilities some of which are very similar to the clinical signs of MS. Thus there is an immediate need to understand the mechanisms that trigger inflammation in the brain that causes MS as well as other neurological diseases. Recent studies from our laboratory have identified a molecule called CD44 which seems to play a critical role in regulating the inflammation in the brain. Thus, the current study will identify the precise role played by this molecule and address how CD44 can be altered to develop novel treatment modality against MS and other neurological diseases. We believe that these studies have a direct impact in promoting Veterans'health.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX001357-02
Application #
8431679
Study Section
Neurobiology C (NURC)
Project Start
2012-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
086371846
City
Columbia
State
SC
Country
United States
Zip Code
29209
Alhasson, Firas; Seth, Ratanesh Kumar; Sarkar, Sutapa et al. (2018) High circulatory leptin mediated NOX-2-peroxynitrite-miR21 axis activate mesangial cells and promotes renal inflammatory pathology in nonalcoholic fatty liver disease. Redox Biol 17:1-15
Seth, Ratanesh Kumar; Kimono, Diana; Alhasson, Firas et al. (2018) Increased butyrate priming in the gut stalls microbiome associated-gastrointestinal inflammation and hepatic metabolic reprogramming in a mouse model of Gulf War Illness. Toxicol Appl Pharmacol 350:64-77
Seth, Ratanesh K; Das, Suvarthi; Dattaroy, Diptadip et al. (2017) TRPV4 activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity. Free Radic Biol Med 102:260-273
Singh, Narendra P; Singh, Udai P; Rouse, Michael et al. (2016) Dietary Indoles Suppress Delayed-Type Hypersensitivity by Inducing a Switch from Proinflammatory Th17 Cells to Anti-Inflammatory Regulatory T Cells through Regulation of MicroRNA. J Immunol 196:1108-22
Sido, Jessica M; Jackson, Austin R; Nagarkatti, Prakash S et al. (2016) Marijuana-derived ?-9-tetrahydrocannabinol suppresses Th1/Th17 cell-mediated delayed-type hypersensitivity through microRNA regulation. J Mol Med (Berl) 94:1039-51
Sido, Jessica M; Nagarkatti, Prakash S; Nagarkatti, Mitzi (2016) Production of endocannabinoids by activated T cells and B cells modulates inflammation associated with delayed-type hypersensitivity. Eur J Immunol 46:1472-9
Bam, Marpe; Yang, Xiaoming; Zhou, Juhua et al. (2016) Evidence for Epigenetic Regulation of Pro-Inflammatory Cytokines, Interleukin-12 and Interferon Gamma, in Peripheral Blood Mononuclear Cells from PTSD Patients. J Neuroimmune Pharmacol 11:168-181
Elliott, David M; Nagarkatti, Mitzi; Nagarkatti, Prakash S (2016) 3,39-Diindolylmethane Ameliorates Staphylococcal Enterotoxin B–Induced Acute Lung Injury through Alterations in the Expression of MicroRNA that Target Apoptosis and Cell-Cycle Arrest in Activated T Cells. J Pharmacol Exp Ther 357:177-87
Bam, Marpe; Yang, Xiaoming; Zumbrun, Elizabeth E et al. (2016) Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation. Sci Rep 6:31209
Chandrashekaran, Varun; Das, Suvarthi; Seth, Ratanesh Kumar et al. (2016) Purinergic receptor X7 mediates leptin induced GLUT4 function in stellate cells in nonalcoholic steatohepatitis. Biochim Biophys Acta 1862:32-45

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