Abstract
Theiler’s murine encephalomyelitis virus (TMEV) infection represents an experimental mouse model to study hippocampal damage induced by neurotropic viruses. IL-10 is a pleiotropic cytokine with profound anti-inflammatory properties, which critically controls immune homeostasis. In order to analyze IL-10R signaling following virus-induced polioencephalitis, SJL mice were intracerebrally infected with TMEV. RNA-based next generation sequencing revealed an up-regulation of Il10, Il10rα and further genes involved in IL-10 downstream signaling, including Jak1, Socs3 and Stat3 in the brain upon infection. Subsequent antibody-mediated blockade of IL-10R signaling led to enhanced hippocampal damage with neuronal loss and increased recruitment of CD3+ T cells, CD45R+ B cells and an up-regulation of Il1α mRNA. Increased expression of Tgfβ and Foxp3 as well as accumulation of Foxp3+ regulatory T cells and arginase-1+ macrophages/microglia was detected in the hippocampus, representing a potential compensatory mechanism following disturbed IL-10R signaling. Additionally, an increased peripheral Chi3l3 expression was found in spleens of infected mice, which may embody reactive regulatory mechanisms for prevention of excessive immunopathology. The present study highlights the importance of IL-10R signaling for immune regulation and its neuroprotective properties in the context of an acute neurotropic virus infection.
Highlights
Theiler’s murine encephalomyelitis virus (TMEV), a neurotropic picornavirus, preferentially targets limbic and temporal structures, including the hippocampus, during acute infection in mice[1,2]
To determine the kinetics of Il10 and related genes involved in IL-10 downstream signaling during the course of acute TMEV infection, RNA-based next generation sequencing (RNA-Seq) of brain tissue was performed
Gene-wise comparison showed a significant upregulation of Il10, Il10rα, Jak[1] and Stat[3] expression at 7 dpi compared to 4 dpi (p = 0.009 for all genes) and a significant downregulation of the same transcripts at 14 dpi compared to 7 dpi (p = 0.009 for all genes; Fig. 1c–f)
Summary
Theiler’s murine encephalomyelitis virus (TMEV), a neurotropic picornavirus, preferentially targets limbic and temporal structures, including the hippocampus, during acute infection in mice[1,2]. IL-10 is a pleiotropic cytokine with profound anti-inflammatory and tolerogenic properties, which is produced by resident microglia, CNS-infiltrating macrophages and lymphocytes, regulatory T cells (Treg), in inflammatory disorders[9] It is crucial for maintenance of immune homeostasis and plays a central role in a variety of human diseases[10,11,12]. In contrast to the predominantly therapeutic effect of IL-10 in autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE)[10], an ambivalent and more complex function of IL-10R signaling has been described in infectious CNS disorders. Both beneficial and detrimental effects can be observed. The aim of the present study was (i) to perform an expressional analysis of IL-10R signaling during the course of TMEV-induced polioencephalitis in SJL mice and (ii) to determine the effects of IL-10R blockade on hippocampal pathology during early TME in SJL mice
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