Increase of Pro-Inflammatory Cytokine Expression in Non-Demyelinating Early Cerebral Lesions in Nervous Canine Distemper

Beineke, Andreas; Markus, Stefanie; Borlak, Jürgen; Thum, Thomas; Baumgärtner, Wolfgang

doi:10.1089/vim.2008.0043

Cited by 22 publications

(23 citation statements)

References 58 publications

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“…Similar to TME, experimental spinal cord injury in mice leads to microglial polarization into a pro-inflammatory and neurotoxic M1 phenotype, which might function as an early trigger of degeneration and immunological events at later disease stages (34). Excessive microglial responses can be observed also in human and canine spinal cord trauma, which leads to potentially destructive effects by the release of pro-inflammatory cytokines, proteolytic molecules and reactive oxygen species (2,3,19,52,70,80,81). Taken together, an imbalance toward M1 dominance represents a potential prerequisite for lesion initiation in TME as currently discussed for MS (21).…”

Section: Discussionmentioning

confidence: 99%

Dynamic Changes of Microglia/Macrophage M1 and M2 Polarization in Theiler's Murine Encephalomyelitis

Herder¹,

Iskandar²,

Kegler³

et al. 2015

Brain Pathology

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Microglia and macrophages play a central role for demyelination in Theiler's murine encephalomyelitis (TME) virus infection, a commonly used infectious model for chronic-progressive multiple sclerosis. In order to determine the dynamic changes of microglia/macrophage polarization in TME, the spinal cord of Swiss Jim Lambert (SJL) mice was investigated by gene expression profiling and immunofluorescence. Virus persistence and demyelinating leukomyelitis were confirmed by immunohistochemistry and histology. Electron microscopy revealed continuous myelin loss together with abortive myelin repair during the late chronic infection phase indicative of incomplete remyelination. A total of 59 genes out of 151 M1- and M2-related genes were differentially expressed in TME virus-infected mice over the study period. The onset of virus-induced demyelination was associated with a dominating M1 polarization, while mounting M2 polarization of macrophages/microglia together with sustained prominent M1-related gene expression was present during the chronic-progressive phase. Molecular results were confirmed by immunofluorescence, showing an increased spinal cord accumulation of CD16/32(+) M1-, arginase-1(+) M2- and Ym1(+) M2-type cells associated with progressive demyelination. The present study provides a comprehensive database of M1-/M2-related gene expression involved in the initiation and progression of demyelination supporting the hypothesis that perpetuating interaction between virus and macrophages/microglia induces a vicious circle with persistent inflammation and impaired myelin repair in TME.

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Section: Discussionmentioning

confidence: 99%

Dynamic Changes of Microglia/Macrophage M1 and M2 Polarization in Theiler's Murine Encephalomyelitis

Herder¹,

Iskandar²,

Kegler³

et al. 2015

Brain Pathology

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“…In addition to dominating expression of pro-inflammatory cytokines, additional events such as disruption of the BBB may represent necessary factors to cause obvious histopathological changes during CDV-DL [60,61]. In this respect, a number of recent studies have highlighted MMPs and their inhibitors as additional crucial proteins in the molecular pathogenesis of nervous distemper [61,62,63].…”

Section: Canine Distemper Leukoencephalitis — Novel Aspects Of Itsmentioning

confidence: 99%

New Aspects of the Pathogenesis of Canine Distemper Leukoencephalitis

Lempp

Spitzbarth

Puff

et al. 2014

Viruses

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Canine distemper virus (CDV) is a member of the genus morbillivirus, which is known to cause a variety of disorders in dogs including demyelinating leukoencephalitis (CDV-DL). In recent years, substantial progress in understanding the pathogenetic mechanisms of CDV-DL has been made. In vivo and in vitro investigations provided new insights into its pathogenesis with special emphasis on axon-myelin-glia interaction, potential endogenous mechanisms of regeneration, and astroglial plasticity. CDV-DL is characterized by lesions with a variable degree of demyelination and mononuclear inflammation accompanied by a dysregulated orchestration of cytokines as well as matrix metalloproteinases and their inhibitors. Despite decades of research, several new aspects of the neuropathogenesis of CDV-DL have been described only recently. Early axonal damage seems to represent an initial and progressive lesion in CDV-DL, which interestingly precedes demyelination. Axonopathy may, thus, function as a potential trigger for subsequent disturbed axon-myelin-glia interactions. In particular, the detection of early axonal damage suggests that demyelination is at least in part a secondary event in CDV-DL, thus challenging the dogma of CDV as a purely primary demyelinating disease. Another unexpected finding refers to the appearance of p75 neurotrophin (NTR)-positive bipolar cells during CDV-DL. As p75NTR is a prototype marker for immature Schwann cells, this finding suggests that Schwann cell remyelination might represent a so far underestimated endogenous mechanism of regeneration, though this hypothesis still remains to be proven. Although it is well known that astrocytes represent the major target of CDV infection in CDV-DL, the detection of infected vimentin-positive astrocytes in chronic lesions indicates a crucial role of this cell population in nervous distemper. While glial fibrillary acidic protein represents the characteristic intermediate filament of mature astrocytes, expression of vimentin is generally restricted to immature or reactive astrocytes. Thus, vimentin-positive astrocytes might constitute an important cell population for CDV persistence and spread, as well as lesion progression. In vitro models, such as dissociated glial cell cultures, as well as organotypic brain slice cultures have contributed to a better insight into mechanisms of infection and certain morphological and molecular aspects of CDV-DL. Summarized, recent in vivo and in vitro studies revealed remarkable new aspects of nervous distemper. These new perceptions substantially improved our understanding of the pathogenesis of CDV-DL and might represent new starting points to develop novel treatment strategies.

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“…Due to the morphological similarities between the neuropathological changes in DL and Multiple Sclerosis (MS), nervous distemper advanced to an important spontaneously occurring animal model of human demyelinating diseases (3,11,49). Initiation of demyelination has been ascribed to a direct action of the virus, infiltrating CD8-positive cytotoxic T cells and an upregulation of proinflammatory cytokines (4,17,20). Demyelination in DL is supposed to be a biphasic process.…”

Section: Introductionmentioning

confidence: 99%

Axonal Pathology and Loss Precede Demyelination and Accompany Chronic Lesions in a Spontaneously Occurring Animal Model of Multiple Sclerosis

Seehusen

Baumgärtner

2010

Brain Pathology

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Axonal damage has been highlighted recently as a cause of neurological disability in various demyelinating diseases, including multiple sclerosis, either as a primary pathological change or secondary due to myelin loss. To characterize and quantify axonal damage and loss in canine distemper demyelinating leukoencephalomyelitis (DL), formalin-fixed paraffin-embedded cerebella were investigated histochemically and immunohistochemically using the modified Bielschowsky's silver stain as well as antibodies against nonphosphorylated (n-NF), phosphorylated neurofilament (p-NF) and beta-amyloid precursor protein (beta-APP). Injured axons characterized by immunoreactivity against n-NF and beta-APP were detected in early distemper lesions without demyelination. In subacute and chronic demyelinating lesions the number of injured axons increased. Moreover, a significant decrease in axonal density was observed within lesions and in the normal appearing white matter in DL as determined by morphometric analyses using Bielschowsky's silver stain and p-NF immunohistochemistry. Summarized, the observed findings indicate that axonal damage (i) occurs early in DL; (ii) can be detected before myelin loss; and (iii) represents a pivotal feature in advanced lesions. It must be postulated that axonal damage plays an important role in the initial phase as a primary event and during progression of nervous distemper as a result of demyelination.

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Increase of Pro-Inflammatory Cytokine Expression in Non-Demyelinating Early Cerebral Lesions in Nervous Canine Distemper

Cited by 22 publications

References 58 publications

Dynamic Changes of Microglia/Macrophage M1 and M2 Polarization in Theiler's Murine Encephalomyelitis

Dynamic Changes of Microglia/Macrophage M1 and M2 Polarization in Theiler's Murine Encephalomyelitis

New Aspects of the Pathogenesis of Canine Distemper Leukoencephalitis

Axonal Pathology and Loss Precede Demyelination and Accompany Chronic Lesions in a Spontaneously Occurring Animal Model of Multiple Sclerosis

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