The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis

Cusick, Matthew F.; Libbey, Jane E.; Doty, Daniel J.; DePaula-Silva, Ana Beatriz; Fujinami, Robert S.

doi:10.1007/s13365-017-0554-8

Cited by 21 publications

(18 citation statements)

References 20 publications

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“…2 is supported by data obtained using a 32×3 Custom RT 2 Profiler PCR array (Qiagen) (Libbey et al 2017). Because seizures start as early as day 3 p.i., independent of the peak of viral replication but dependent on IL-6 (Cusick et al 2017; Libbey et al 2011a), it suggests that seizures are occurring due to activation of the innate immune response.…”

Section: Discussionmentioning

confidence: 99%

The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

DePaula-Silva

Sonderegger²,

Libbey

et al. 2018

J. Neurovirol.

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Viral infection of the central nervous system can result in encephalitis. About 20% of individuals who develop viral encephalitis go on to develop epilepsy. We have established an experimental model where virus infection of mice with Theiler's murine encephalomyelitis virus (TMEV) leads to acute seizures, followed by a latent period (no seizures/epileptogenesis phase) and then spontaneous recurrent seizures-epilepsy. Infiltrating macrophages (CD11bCD45) present in the brain at day 3 post-infection are an important source of interleukin-6, which contributes to the development of acute seizures in the TMEV-induced seizure model. Time course analysis of viral infection and inflammatory [CD11bCD45Ly-6C] and patrolling [CD11bCD45Ly-6C] monocyte and T cell infiltration into the brains of TMEV-infected C57BL/6J mice over the entire course of the acute viral infection was performed to elucidate the role of virus and the immune response to virus in seizures and viral clearance. The infiltrating inflammatory macrophages were present early following infection but declined over the course of acute viral infection, supporting a role in seizure development, while the lymphocyte infiltration increased rapidly and plateaued, advocating that they play a role in viral clearance. In addition, we showed for the first time that, while TMEV infection of RAG1 mice did not alter the number of mice experiencing acute seizures, TMEV infection of C57BL/6J mice depleted of macrophages resulted in a significant decrease in the number of mice experiencing seizures, again supporting a role for infiltrating macrophages in the development of acute seizures in the TMEV-induced seizure model.

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Section: Discussionmentioning

confidence: 99%

The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

DePaula-Silva

Sonderegger²,

Libbey

et al. 2018

J. Neurovirol.

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“…And the latter was implicated in negatively affecting the integrity of the blood brain barrier [ 3 , 4 ]. The remaining 30% of CD45 + /CD11b + cells were not investigated further, based on previous reports we assume that they might be infiltrating macrophages [ 30 – 33 ]. As for the early phase following pilocarpine-induced status epilepticus, our data are in line with previous reports and confirm that pilocarpine induces the activation of hippocampal microglia [ 1 , 21 , 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Mycophenolate mofetil prevents the delayed T cell response after pilocarpine-induced status epilepticus in mice

et al. 2017

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Growing clinical and laboratory evidence corroborates a role for the immune system in the pathophysiology of epilepsy. In order to delineate the immune response following pilocarpine-induced status epilepticus (SE) in the mouse, we monitored the kinetics of leukocyte presence in the hippocampus over the period of four weeks. SE was induced following a ramping protocol of pilocarpine injection into 4–5 weeks old C57BL/6 mice. Brains were removed at days 1–4, 14 or 28 after SE, and the hippocampi were analyzed via flow cytometry, via quantitative reverse transcriptase PCR (qRT-PCR) and via immunohistochemistry. Epileptogenesis was confirmed by Timm staining of mossy fiber sprouting in the inner molecular layer of the dentate gyrus. The flow cytometry data revealed a biphasic immune response following pilocarpine-induced SE with a transient increase in activated CD11b+ and F4/80+ macrophages within the first four days replaced by an increase in CD3+ T-lymphocytes around day 28. This delayed T cell response was confirmed via qRT-PCR and via immunohistochemistry. In addition, qRT-PCR data could show that the delayed T cell response was associated with an increased CD8/CD4 ratio indicating a cytotoxic T cell response after SE. Intriguingly, early intervention with mycophenolate mofetil administration on days 0–3 after SE prevented this delayed T cell response. These results show an orchestrated immunological sequela and provide evidence that the delayed T cell response is sensitive to early immunomodulatory intervention.

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“…Furthermore, C57BL/6 mice with seizures have higher TNFα and IL6 mRNA brain levels compared to non-seizing mice [98]. The fact that TMEV-DA-infected IL6 knockout mice treated with recombinant IL6 also developed seizures demonstrated the ability of pathological IL6 levels in the periphery to cause seizures [176]. In addition to pro-inflammatory cytokines, the complement component C3 participates in the induction of acute seizures following the TMEV-DA infection of C57BL/6 mice [177].…”

Section: Innate Immunity In Theiler’s Murine Encephalomyelitis Virmentioning

confidence: 99%

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

Gerhauser

Hansmann

Ciurkiewicz

et al. 2019

IJMS

104

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Theiler’s murine encephalomyelitis virus (TMEV), a naturally occurring, enteric pathogen of mice is a Cardiovirus of the Picornaviridae family. Low neurovirulent TMEV strains such as BeAn cause a severe demyelinating disease in susceptible SJL mice following intracerebral infection. Furthermore, TMEV infections of C57BL/6 mice cause acute polioencephalitis initiating a process of epileptogenesis that results in spontaneous recurrent epileptic seizures in approximately 50% of affected mice. Moreover, C3H mice develop cardiac lesions after an intraperitoneal high-dose application of TMEV. Consequently, TMEV-induced diseases are widely used as animal models for multiple sclerosis, epilepsy, and myocarditis. The present review summarizes morphological lesions and pathogenic mechanisms triggered by TMEV with a special focus on the development of hippocampal degeneration and seizures in C57BL/6 mice as well as demyelination in the spinal cord in SJL mice. Furthermore, a detailed description of innate and adaptive immune responses is given. TMEV studies provide novel insights into the complexity of organ- and mouse strain-specific immunopathology and help to identify factors critical for virus persistence.

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The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis

Cited by 21 publications

References 20 publications

The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

The immune response to picornavirus infection and the effect of immune manipulation on acute seizures

Mycophenolate mofetil prevents the delayed T cell response after pilocarpine-induced status epilepticus in mice

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

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