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

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.

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

“…A recent study demonstrated that the severity of hippocampal neurodegeneration, the number of activated microglia/macrophages, and the ISG15 expression almost perfectly discriminate seizing from non-seizing C57BL/6 mice after a TMEV-DA infection despite the fact that strong microglia/macrophage activation and some hippocampal damage are also present in SJL mice [23]. Limited hippocampal damage in TMEV-BeAn-infected SJL mice might be caused by the induction of IL10 receptor signaling, which exhibits anti-inflammatory and neuroprotective properties [162,163,164]. No difference between SJL and C57BL/6 mice can be found in the TGFβ1 gene expression during acute polioencephalomyelitis, but seized C57BL/6 mice show a strong TGFβ expression in hippocampal neurons, which is not present in unseized C57BL/6 mice or mock- and TMEV-DA-infected SJL mice [2,164].…”

“…In TMEV-DA-infected mice, IL1β does not seem to play a major role in seizures because IL1 receptor I- and MyD88-deficient C57BL/6 mice have a seizure frequency similar to wild type mice. In contrast, only 10% of TNF receptor I- and 15% of IL6-deficient C57BL/6 mice showed signs of seizure activity, and fewer seizures are seen in TNFα −/− mice bred on a C57BL/6 background [98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,…”

Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis

“…In the TMEV-mediated transient polioencephalitis model using SJL mice, peak virus load in the hippocampus coincides with peak expression of IL-10, IL-10ra , and relates genes. IL-10R neutralization resulted in increased loss of mature neurons and axonal damage, which correlated with enhanced inflammation, although virus load was not altered (65). Further, increased accumulation of Foxp3 Tregs and arginase-1 expressing microglia/macrophages suggested unsuccessful efforts of the host to compensate for the abrogated IL-10 signaling.…”

Mutations in VP0 and 2C Proteins of Duck Hepatitis A Virus Type 3 Attenuate Viral Infection and Virulence

“…IL-10 is mostly regarded as an anti-inflammatory cytokine that plays a central role in a variety of human diseases through the maintenance of immune homeostasis [72]. Previous studies have revealed that Il-10 can prevent hepatic steatosis and other metabolic abnormalities with anti-inflammatory, immunosuppressive, tolerogenic, and neuroprotective properties [73,74,75]. The mechanism employed by the attenuated strain of DHAV-3 to stimulate anti-inflammatory cytokines remains unclear.…”