Viral Infection of the Central Nervous System Exacerbates Interleukin-10 Receptor Deficiency-Mediated Colitis in SJL Mice

Parasite co-evolution alongside the mammalian immune system gave rise to several modulatory strategies by which they prevent exaggerated pathology and facilitate a longer worm survival. As little is known about the immunoregulatory potential of the zoonotic canine parasites Ancylostoma caninum and Toxocara canis in the natural host, the present study aimed to investigate whether their larval excretory-secretory (ES) products can modulate the canine immune system. We demonstrated TcES to increase the frequency of CD4+ Foxp3high T cells, while both AcES and TcES were associated with elevated Helios expression in Foxp3high lymphocytes. ES products were further capable of inducing IL-10 production by lymphocytes, which was mainly attributed to CD8+ T cells. ES treatment of PBMCs prior to mitogen stimulation inhibited polyclonal proliferation of CD4+ and CD8+ T cells. Moreover, monocyte-derived ES-pulsed dendritic cells reduced upregulation of MHC-II and CD80 in response to lipopolysaccharide. The data showed that regulation of the canine immune system by A. caninum and T. canis larvae comprises the modification of antigen-specific and polyclonal T cell responses and dendritic cell maturation.

Section: Discussionmentioning

confidence: 99%

Zoonotic intestinal helminths interact with the canine immune system by modulating T cell responses and preventing dendritic cell maturation

Junginger

Raue

Wolf

et al. 2017

“…25 five-week old female SJL and 5 five-week old female C57BL/6 mice (Harlan Winkelmann) were inoculated with 1.63 × 10 6 PFU of TMEV (BeAn-strain, 0 days post infection [dpi]) into the right cerebral hemisphere following general anesthesia, as described previously 25 . In the first experiment, necropsy was performed in groups of five SJL animals at 4, 7 and 14 dpi, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Our previous studies on IL-10 in TME revealed only limited effects of anti-IL-10R treatment on spinal cord lesions and virus load in SJL mice during the chronic disease 25 . In acute TME, an elevated Il10 expression primarily by infiltrating T cells was observed in the brain of SJL mice compared to those of seizure-prone C57BL/6 mice 26 .…”

Section: Introductionmentioning

confidence: 91%

Intact interleukin-10 receptor signaling protects from hippocampal damage elicited by experimental neurotropic virus infection of SJL mice

Uhde¹,

Ciurkiewicz²,

Herder³

et al. 2018

Self Cite

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.

“…In experiment 4, also hematoxylin + eosin (HE)-stained sections (at −1.7 to −1.82 mm from bregma) were used to measure hypercellularity in the hippocampus after kainate. The extent of hypercellularity was scored as described previously 44 : 1 = 1–25 cells, 2 = 26–50 cells, 3 = > 50 cells per high power field.…”

Section: Methodsmentioning

confidence: 99%

A combination of NMDA and AMPA receptor antagonists retards granule cell dispersion and epileptogenesis in a model of acquired epilepsy

Schidlitzki¹,

Twele²,

Klee³

et al. 2017

Epilepsy may arise following acute brain insults, but no treatments exist that prevent epilepsy in patients at risk. Here we examined whether a combination of two glutamate receptor antagonists, NBQX and ifenprodil, acting at different receptor subtypes, exerts antiepileptogenic effects in the intrahippocampal kainate mouse model of epilepsy. These drugs were administered over 5 days following kainate. Spontaneous seizures were recorded by video/EEG at different intervals up to 3 months. Initial trials showed that drug treatment during the latent period led to higher mortality than treatment after onset of epilepsy, and further, that combined therapy with both drugs caused higher mortality at doses that appear safe when used singly. We therefore refined the combined-drug protocol, using lower doses. Two weeks after kainate, significantly less mice of the NBQX/ifenprodil group exhibited electroclinical seizures compared to vehicle controls, but this effect was lost at subsequent weeks. The disease modifying effect of the treatment was associated with a transient prevention of granule cell dispersion and less neuronal degeneration in the dentate hilus. These data substantiate the involvement of altered glutamatergic transmission in the early phase of epileptogenesis. Longer treatment with NBQX and ifenprodil may shed further light on the apparent temporal relationship between dentate gyrus reorganization and development of spontaneous seizures.