Abstract
BackgroundExperimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS). It has been shown that Th17 cells are critical for EAE pathogenesis. Mice lacking CXCR3 develop aggravated EAE compared with wild-type (WT) mice. This study investigated the effect of CXCR3 on Th17 expansion during EAE and further addressed the underlying mechanism.MethodsBoth active EAE and adoptive-transfer EAE experiments were employed for studying EAE pathogenesis in WT and CXCR3−/− mice. Demyelination and leukocyte infiltration in the spinal cord of mice were analyzed by luxol fast blue staining and flow cytometry analysis, respectively. Glial cells expressing CXCR3 in the spinal cord were analyzed by immunofluorescence staining. Cytokine and chemokine levels in the spinal cord were analyzed using quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). The glial cell line U87MG was employed for studying the CXCR3 signaling-mediated mechanism regulating Th17 expansion.ResultsCXCR3−/− mice exhibited more severe EAE and had significantly increased central nervous system (CNS)-infiltrating Th17 cells compared with WT mice. Adoptive-transfer experiments showed that CXCR3−/− recipient mice that received Th17 cells polarized from splenocytes of myelin oligodendrocyte glycoprotein (MOG)-immunized CXCR3−/− mice or MOG-immunized WT mice always developed more severe EAE and had significantly increased CNS-infiltrating Th17 cells compared with WT recipient mice that received Th17 cells from the same origin. Furthermore, during EAE, the number of activated glial cells was increased in the CNS of MOG-immunized CXCR3−/− mice, and CXCR3-deficient glial cells expressed increased levels of cytokine genes required for Th17 expansion and recruitment. Finally, we found that extracellular signal-regulated kinase (ERK) activation elicited by CXCR3 signaling in U87MG cells attenuated the activation of NF-κB, a key transcription factor critical for the induction of IL-23 and CCL20, which are required for Th17 cell expansion and recruitment, respectively.ConclusionsThis study demonstrates a previously unrecognized role of CXCR3 signaling in glial cells in negatively regulating Th17 cell expansion during EAE. Our results demonstrate that, in addition to its well-known role in the recruitment of immune cells, CXCR3 in CNS glial cells plays a critical role in restraining the pro-Th17 cytokine/chemokine milieu during EAE, thereby diminishing Th17 cell expansion in the CNS and suppressing disease development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0536-4) contains supplementary material, which is available to authorized users.
Highlights
Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS)
Th17 cells compared with WT recipient mice in adoptivetransfer EAE Given that CXCR3−/− mice show more severe EAE and significantly increased infiltrating Th17 cells (Fig. 2), and that disease severity in CXCR3−/− mice is associated with the central nervous system (CNS) milieu (Fig. 3), we investigated whether the CNS milieu in CXCR3−/− was favorable for CNS
Cytokines required for Th17 expansion and recruitment are significantly increased in the spinal cord in CXCR3−/− mice compared with WT mice Having found that a CXCR3-deficient CNS milieu promotes Th17 cell expansion (Figs. 4 and 5), we examined whether a CXCR3 deficiency generates a CNS microenvironment preferential for Th17 proliferation, survival, maintenance, and recruitment
Summary
Experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS). Because IL-23 is critical for the maintenance, survival, and proliferation of Th17 cells [8, 9], this T cell subtype has since been thought to play a pivotal role in the development of EAE Consistent with this idea, mice lacking IL17 or RORγt, a transcription factor for Th17 cells, and mice treated with an IL-17 blocking antibody are less susceptible to EAE [9,10,11]. Autoreactive Th17 cells preferentially expressing CCR6 have been shown to trigger the initial inflammation by entering the CNS through the choroid plexus via a CCR6-CCL20dependent mechanism and further infiltrating the CNS parenchyma by a CCR6-independent mechanism [12] In accord with these findings, studies in human patients have shown that Th17 cells are involved in MS [13, 14]
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