Sema4A inhibits the therapeutic effect of IFN-β in EAE
Introduction
Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that causes neurological disability in young adults (Noseworthy et al., 2000). Although several disease-modifying drugs (DMDs) have been developed (Ransohoff, 2007, Pelletier and Hafler, 2012, Sempere et al., 2013), interferon-beta (IFN-β) remains one of the most prescribed treatments for relapsing-remitting multiple sclerosis (RRMS). IFN-β therapy reduces overall relapse rates by approximately 30% and improves prognosis (Rudick and Goelz, 2011).
The mechanisms of action of IFN-β have been studied utilizing experimental autoimmune encephalomyelitis (EAE), an animal model of MS, along with assessment of clinical responses to IFN-β therapy in humans. The mechanisms of action of IFN-β involve multiple immunoregulatory functions, including blocking the trafficking of lymphocytes to the CNS (Floris et al., 2002), reducing expression of major histocompatibility class II molecules (Jiang et al., 1995), attenuating T cell proliferation and altering the cytokine milieu from pro-inflammatory to anti-inflammatory (Mcrae et al., 1998, Kozovska et al., 1999, Ramgolam et al., 2009).
Although IFN-β therapy is safe and generally well tolerated, a major problem with this therapy is that approximately one-third of patients with MS do not respond to the therapy (Rio et al., 2006). Because early initiation of appropriate treatments is necessary for a better prognosis (Kappos et al., 2007), distinguishing responders from non-responders prior to the initiation of treatment is critical. Although no established biomarkers exist that predict responsiveness to IFN-β, Th17-skewing are suggested to be related to IFN-β resistance (Lee et al., 2011, Balasa et al., 2013). We previously reported that high levels of serum Sema4A are correlated with nonresponsiveness to IFN-β therapy (Nakatsuji et al., 2012). However, the underlying mechanisms of how Sema4A affects the response to IFN-β remain unknown.
Sema4A is a membrane-type class IV semaphorin that we originally identified using a dendritic cell cDNA library (Kumanogoh et al., 2002). Although semaphorins were originally identified as axon guidance molecules that act during neural development, Sema4A also plays a crucial role in the immune and vascular systems (Kumanogoh et al., 2002, Kumanogoh et al., 2005, Toyofuku et al., 2007). In the immune system, Sema4A activates Th cells and promotes differentiation of Th1 and Th17 cells, whereas it is involved in angiogenesis and migration of endothelial cells by modulating vascular endothelial growth factor signaling in the vascular system (Toyofuku et al., 2007, Meda et al., 2012). Consistent with its important role in Th cells, Sema4A has been implicated in EAE. Treatment with anti-Sema4A antibodies inhibits antigen-specific T cell generation and ameliorates EAE (Kumanogoh et al., 2002). In addition, Sema4A is increased in the sera of patients with MS (Nakatsuji et al., 2012). These data together suggest that Sema4A plays critical roles in both MS and EAE.
In this study, we investigated whether recombinant Sema4A abrogates the efficacy of IFN-β in the EAE model of MS and analyzed the underlying mechanisms.
Section snippets
Animals & reagents
Wild-type C57BL/6 female mice were purchased from Oriental Yeast Corp. (Tokyo, Japan) and were maintained in a specific pathogen-free environment. Experimental procedures were approved by the Animal Care and Use Committee of Osaka University Graduate School of Medicine (Permit Number: 20-084-6). All possible efforts were made to minimize animal suffering and limit the number of animals used. Recombinant murine IFN-β (PBL Biomedical Laboratories, Piscataway, NJ) and recombinant human IFN-β 1b
Sema4A promotes Th1 and Th17 differentiation in the presence of IFN-β
Induction of myelin-reactive Th1 and Th17 cells is the first crucial step for the initiation and progression of EAE and MS (Ishizu et al., 2005, Goverman, 2009). IFN-β suppresses the differentiation of these cells (Guo et al., 2008, Durelli et al., 2009, Zhang et al., 2011). To investigate the association between Sema4A and IFN-β in Th1 and Th17 differentiation, we first immunized C57BL/6 mice with MOG35–55 and treated them with recombinant Sema4A-Fc in the presence of IFN-β. CD4+ T cells were
Discussion
In the current study, we investigated the implications of Sema4A on the efficacy of IFN-β by administering recombinant Sema4A-Fc and IFN-β to mice with EAE.
IFN-β confers its beneficial effect in MS and EAE through pleiotropic mechanisms of action. Among these, suppression of encephalitogenic T cells is one of the most important mechanisms. Reduction of T cell activation and proliferation, and induction of a shift toward anti-inflammatory cytokines have been shown to contribute to the efficacy
Acknowledgments
This study was partly supported by the Health and Labor Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan.
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These authors contributed equally to this work.