Endothelin-1 contributes to the development of virus-induced demyelinating disease
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RESEARCH
Open Access
Endothelin-1 contributes to the development of virus-induced demyelinating disease Young-Hee Jin1,2,3* , Bongsu Kang1, Hyun S. Kang1, Chang-Sung Koh4 and Byung S. Kim1*
Abstract Background: Experimental autoimmune encephalitis (EAE) and virally induced demyelinating disease are two major experimental model systems used to study human multiple sclerosis. Although endothelin-1 level elevation was previously observed in the CNS of mice with EAE and viral demyelinating disease, the potential role of endothelin-1 in the development of these demyelinating diseases is unknown. Methods and results: In this study, the involvement of endothelin-1 in the development and progression of demyelinating diseases was investigated using these two experimental models. Administration of endothelin-1 significantly promoted the progression of both experimental diseases accompanied with elevated inflammatory T cell responses. In contrast, administration of specific endothelin-1 inhibitors (BQ610 and BQ788) significantly inhibited progression of these diseases accompanied with reduced T cell responses to the respective antigens. Conclusions: These results strongly suggest that the level of endothelin-1 plays an important role in the pathogenesis of immune-mediated CNS demyelinating diseases by promoting immune responses. Keywords: CNS, EAE, TMEV, Endothelin-1, Demyelination
Introduction Theiler’s murine encephalomyelitis virus (TMEV) causes a chronic progressive demyelinating disease in susceptible mice [1, 2]. Development of this virally induced demyelinating disease appears to be immune-mediated and primarily involves CD4+ T cells [3, 4]. Infiltration of proinflammatory T cells such as Th17 and Tc17 appears to be associated with tissue destruction and demyelination [5, 6], similar to multiple sclerosis (MS) [7–9]. In addition, both T cell and antibody responses to selfantigens are induced in susceptible mice after chronic TMEV infection [10–13]. Therefore, this viral demyelinating disease model in mice has been investigated as a relevant animal model for MS. Infection of cells with * Correspondence: [email protected]; [email protected] 1 Department of Microbiology-Immunology, Northwestern University Feinberg Medical School, 303 East Chicago Avenue, Chicago, IL 60611, USA Full list of author information is available at the end of the article
TMEV activates production of various cytokines via TLR- and melanoma differentiation-associated gene 5 (MDA5)-dependent pathways [14–16]. High levels of IL1 or type I IFNs, which are downstream products of TLR or MDA5 activation, play a pathogenic role [17, 18]. Similarly, excessive levels of IL-6 exert a potent pathogenic effect on the development of TMEV-induced demyelinating disease by promoting Th17 responses [5]. Furthermore, TLR-mediated signals induce PGE2 elevation via the NLRP3 pathway to affect the pathogenesis of TMEV-induced demyelinating disease [19]. Moreover, TMEV infection activates production of various chemokines in different glial cell types [20, 21]
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