Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by myelin loss, varying degrees of axonal damage, and progressive neurological dysfunction. MS is the most common disabling neurologic disease of young adults and adolescents affecting ~350,000 individuals in the United States and more than 1 million individuals worldwide. Current MS disease-modifying therapies (DMTs) have limited efficacy and untoward toxicities, underscoring the need for new approaches based on targeting underlying disease mechanisms. The p38 mitogen-activated kinase (MAPK) is a central molecule in autoimmune/inflammatory responses in diseases such as rheumatoid arthritis (RA) and Crohn's disease, and inhibition of p38 MAPK is currently being explored clinically as a DMT for these diseases. However, the role of p38 MAPK in the pathophysiology of MS (or MS models) and its potential as a therapeutic target has not been investigated. Using experimental allergic encephalomyelitis (EAE), the principal autoimmune model of MS, we tested whether inhibition of p38 MAPK can influence EAE susceptibility and disease progression. Treatment of female mice with the pharmacological p38 MAPK inhibitor, SB203580, either completely prevented disease or halted disease if administered at the onset of clinical signs. Strikingly, male mice were completely unresponsive to treatment. These findings suggest that sex-specific factors contribute to SB203580 mediated inhibition of p38 MAPK activity and EAE susceptibility. In this application, we propose to: 1) determine the molecular and cellular mechanisms targeted by p38 MAPK inhibition in EAE and 2) determine the basis of the sexual dimorphism in the therapeutic response to SB. Understanding the mechanisms of drug action is likely to provide novel, more specific drug targets for MS therapy. The gender dichotomy with regard to efficacy of SB203580 is particularly important, since many autoimmune diseases, including MS, exhibit a female-specific sexual dimorphism in disease susceptibility. The finding that SB203580 is fully capable of selectively inhibiting disease in females provides for the possibility of a unique DMT that selectively targets the increasing female MS patient population. No study to our knowledge has evaluated the DMT potential of inhibiting p38 MAPK in MS, despite the fact that many compounds targeting this pathway are already approved for phase 2 clinical trials in other autoimmune diseases. Further, relatively few studies focus on the basis of sex differences in therapeutic responses in MS or its models. Inhibition of the p38 MAPK pathway may not only provide a novel DMT which selectively targets the increasing female MS patient population, but also will likely provide mechanistic insight relevant to development of additional DMTs for MS, by uncovering new targets for therapeutic intervention.
The objective of this proposal is to explore a new molecular pathway which is likely to be important in the pathogenesis of multiple sclerosis (MS), and understanding of this pathway can yield new therapeutic targets for treatment of this devastating disease. Further, this proposal explores the bases for sexual dimorphisms in efficacy of drug treatment in autoimmune disease. This point is highly salient today given the increasing female incidence of MS.
|Bearoff, F; Del Rio, R; Case, L K et al. (2016) Natural genetic variation profoundly regulates gene expression in immune cells and dictates susceptibility to CNS autoimmunity. Genes Immun 17:386-395|
|Krementsov, Dimitry N; Case, Laure K; Hickey, William F et al. (2015) Exacerbation of autoimmune neuroinflammation by dietary sodium is genetically controlled and sex specific. FASEB J 29:3446-57|
|Bearoff, Frank; Case, Laure K; Krementsov, Dimitry N et al. (2015) Identification of genetic determinants of the sexual dimorphism in CNS autoimmunity. PLoS One 10:e0117993|
|Krementsov, Dimitry N; Noubade, Rajkumar; Dragon, Julie A et al. (2014) Sex-specific control of central nervous system autoimmunity by p38 mitogen-activated protein kinase signaling in myeloid cells. Ann Neurol 75:50-66|
|Williams, Cecilia; Bondesson, Maria; Krementsov, Dimitry N et al. (2014) Gestational bisphenol A exposure and testis development. Endocr Disruptors (Austin) 2:|
|Krementsov, Dimitry N; Teuscher, Cory (2013) Environmental factors acting during development to influence MS risk: insights from animal studies. Mult Scler 19:1684-9|
|Krementsov, Dimitry N; Katchy, Anne; Case, Laure K et al. (2013) Studies in experimental autoimmune encephalomyelitis do not support developmental bisphenol a exposure as an environmental factor in increasing multiple sclerosis risk. Toxicol Sci 135:91-102|
|Krementsov, Dimitry N; Thornton, Tina M; Teuscher, Cory et al. (2013) The emerging role of p38 mitogen-activated protein kinase in multiple sclerosis and its models. Mol Cell Biol 33:3728-34|
|Noubade, Rajkumar; Krementsov, Dimitry N; Del Rio, Roxana et al. (2011) Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis. Blood 118:3290-300|