Characterization of the interaction between astrocytes and encephalitogenic lymphocytes during the development of experimental autoimmune encephalitomyelitis (EAE) in mice

Abstract

SummaryThe nature of pathogenic mechanisms associated with the development of multiple sclerosis (MS) have long been debated. However, limited research was conducted to define the interplay between infiltrating lymphocytes and resident cells of the central nervous system (CNS). Data presented in this report describe a novel role for astrocyte-mediated alterations to myelin oligodendrocyte glycoprotein (MOG)35-55-specific lymphocyte responses, elicited during the development of experimental autoimmune encephalitomyelitis (EAE). In-vitro studies demonstrated that astrocytes inhibited the proliferation and interferon (IFN)-g, interleukin (IL)-4, IL-17 and transforming growth factor (TGF)-b secretion levels of MOG35-55-specific lymphocytes, an effect that could be ameliorated by astrocyte IL-27 neutralization. However, when astrocytes were pretreated with IFN-g, they could promote the proliferation and secretion levels of MOG35-55-specific lymphocytes, coinciding with apparent expression of major histocompatibility complex (MHC)-II on astrocytes themselves. Quantitative polymerase chain reaction (qPCR) demonstrated that production of IL-27 in the spinal cord was at its highest during the initial phases. Conversely, production of IFN-g in the spinal cord was highest during the peak phase. Quantitative analysis of MHC-II expression in the spinal cord showed that there was a positive correlation between MHC-II expression and IFN-g production. In addition, astrocyte MHC-II expression levels correlated positively with IFN-g production in the spinal cord. These findings suggested that astrocytes might function as both inhibitors and promoters of EAE. Astrocytes prevented MOG35-55-specific lymphocyte function by secreting IL-27 during the initial phases of EAE. Then, in the presence of higher IFN-g levels in the spinal cord, astrocytes were converted into antigen-presenting cells. This conversion might promote the progression of pathological damage and result in a peak of EAE severity.

Control of autoimmune CNS inflammation by astrocytes

“…Astrocytes, as opposed to microglia and oligodendrocytes, express high levels of IFNGR1(2) in vivo and upregulate MHC-II expression upon stimulation with Interferon-γ in vitro (3), emphasizing their potential function as local antigen presenting cells in the CNS. In this context, early in vitro investigations demonstrated that expression of low levels of MHC-II on non-activated astrocytes results in a decrease of T cell proliferation (4) and induces hyporesponsiveness of T and B cells (5), potentially via secretion of the downmodulatory cytokine IL-27(6,7). In contrast, when activated with Interferon-γ, the ability of astrocytes to produce IL-27 is impaired resulting in increased proliferation and pathogenic potential of MOG-specific T cells ex vivo (6).…”

Interaction of astrocytes and T cells in physiological and pathological conditions

“…Moreover, Lymph node and splenic macrophages of IL-33-treated mice showed polarization toward an alternatively activated macrophage, which are anti-inflammatory. JF Yang et al (Yang et al, 2012a) found that in vitro astrocytes inhibited the proliferation and IFN-γ, IL-4, IL-17 and TGF-β secretion of MOG 35–55 -specific lymphocytes, an effect that could be ameliorated by IL-27 neutralization. However, when astrocytes were pretreated with IFN-γ, they could promote the proliferation and secretion levels of MOG 35–55 -specific lymphocytes.…”

Immune Privilege as an Intrinsic CNS Property: Astrocytes Protect the CNS against T-Cell-Mediated Neuroinflammation

“…The interpretation is supported by a recent study showing that astrocytes inhibited proliferation and IFN- γ , interleukin- (IL-) 4, IL-17, and TGF- β secretion levels of encephalitic T cells in vitro unless they were pretreated with IFN- γ . They even promoted T-cell proliferation, presumably by additional antigen presentation [119]. The inhibitory effect of astrocytes could be ameliorated by IL-27 neutralisation [119].…”

“…They even promoted T-cell proliferation, presumably by additional antigen presentation [119]. The inhibitory effect of astrocytes could be ameliorated by IL-27 neutralisation [119]. IL-27 has been shown to suppress Th17 cells and thereby EAE [120, 121].…”

“…Most of these chemokines attract Th1 cells more than Th2 cells, thus aggravating neuroinflammation. Thus, astrocytes may inhibit and delay neuroinflammation, but in case of sustained inflammation accompanied by high IFN- γ levels, they may switch to become potent APCs and even promotors of inflammation [119]. …”