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Differential Microglial Morphological Response, TNF?, and Viral Load in Sedentary-like and Active Murine Models After Systemic Non-neurotropic Dengue Virus Infection.

ABSTRACT: Peripheral inflammatory stimuli increase proinflammatory cytokines in the bloodstream and central nervous system and activate microglial cells. Here we tested the hypothesis that contrasting environments mimicking sedentary and active lives would be associated with differential microglial morphological responses, inflammatory cytokines concentration, and virus load in the peripheral blood. For this, mice were maintained either in standard (standard environment) or enriched cages (enriched environment) and then subjected to a single (DENV1) serotype infection. Blood samples from infected animals showed higher viral loads and higher tumor necrosis factor-? (TNF?) mRNA concentrations than control subjects. Using an unbiased stereological sampling approach, we selected 544 microglia from lateral septum for microscopic 3D reconstruction. Morphological complexity contributed most to cluster formation. Infected groups exhibited significant increase in the microglia morphological complexity and number, despite the absence of dengue virus antigens in the brain. Two microglial phenotypes (type I with lower and type II with higher morphological complexity) were found in both infected and control groups. However, microglia from infected mice maintained in enriched environment showed only one morphological phenotype. Two-way ANOVA revealed that environmental changes and infection influenced type-I and II microglial morphologies and number. Environmental enrichment and infection interactions may contribute to microglial morphological change to a point that type-I and II morphological phenotypes could no longer be distinguished in infected mice from enriched environment. Significant linear correlation was found between morphological complexity and TNF? peripheral blood. Our findings demonstrated that sedentary-like and active murine models exhibited differential microglial responses and peripheral inflammation to systemic non-neurotropic infections with DENV1 virus.

SUBMITTER: Gomes GF

PROVIDER: S-EPMC6542148 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Differential Microglial Morphological Response, TNFα, and Viral Load in Sedentary-like and Active Murine Models After Systemic Non-neurotropic Dengue Virus Infection.

Gomes Giovanni Freitas GF Peixoto Railana Deise da Fonseca RDDF Maciel Brenda Gonçalves BG Santos Kedma Farias Dos KFD Bayma Lohrane Rosa LR Feitoza Neto Pedro Alves PA Fernandes Taiany Nogueira TN de Abreu Cintya Castro CC Casseb Samir Mansour Moraes SMM de Lima Camila Mendes CM de Oliveira Marcus Augusto MA Diniz Daniel Guerreiro DG Vasconcelos Pedro Fernando da Costa PFDC Sosthenes Marcia Consentino Kronka MCK Diniz Cristovam Wanderley Picanço CWP

The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20190329 6

Peripheral inflammatory stimuli increase proinflammatory cytokines in the bloodstream and central nervous system and activate microglial cells. Here we tested the hypothesis that contrasting environments mimicking sedentary and active lives would be associated with differential microglial morphological responses, inflammatory cytokines concentration, and virus load in the peripheral blood. For this, mice were maintained either in standard (standard environment) or enriched cages (enriched enviro ...[more]

PMID: 30924711

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Project description:BackgroundMicroglia are the primary phagocytes of the central nervous system and are responsible for removing damaged myelin following demyelination. Previous investigations exploring the consequences of myelin phagocytosis on microglial activation overlooked the biochemical modifications present on myelin debris. Such modifications, including citrullination, are increased within the inflammatory environment of multiple sclerosis lesions.MethodsMouse cortical myelin isolated by ultracentrifugation was citrullinated ex vivo by incubation with the calcium-dependent peptidyl arginine deiminase PAD2. Demyelination was induced by 6 weeks of cuprizone (0.3%) treatment and spontaneous repair was initiated by reversion to normal chow. Citrullinated or unmodified myelin was injected into the primary motor cortex above the cingulum bundle at the time of reversion to normal chow and the consequent impact on remyelination was assessed by measuring the surface area of myelin basic protein-positive fibers in the cortex 3 weeks later. Microglial responses to myelin were characterized by measuring cytokine release, assessing flow cytometric markers of microglial activation, and RNAseq profiling of transcriptional changes.ResultsCitrullinated myelin induced a unique microglial response marked by increased tumor necrosis factor α (TNFα) production both in vitro and in vivo. This response was not induced by unmodified myelin. Injection of citrullinated myelin but not unmodified myelin into the cortex of cuprizone-demyelinated mice significantly inhibited spontaneous remyelination. Antibody-mediated neutralization of TNFα blocked this effect and restored remyelination to normal levels.ConclusionsThese findings highlight the role of post-translation modifications such as citrullination in the determination of microglial activation in response to myelin during demyelination. The inhibition of endogenous repair induced by citrullinated myelin and the reversal of this effect by neutralization of TNFα may have implications for therapeutic approaches to patients with inflammatory demyelinating disorders.

Dataset Information

Differential Microglial Morphological Response, TNF?, and Viral Load in Sedentary-like and Active Murine Models After Systemic Non-neurotropic Dengue Virus Infection.

Publications

Differential Microglial Morphological Response, TNFα, and Viral Load in Sedentary-like and Active Murine Models After Systemic Non-neurotropic Dengue Virus Infection.

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