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Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy


Zattoni, M; Mura, M L; Deprez, F; Schwendener, R A; Engelhardt, B; Frei, K; Fritschy, J M (2011). Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. Journal of Neuroscience, 31(11):4037-4050.

Abstract

Clinical and experimental evidence indicates that inflammatory processes contribute to the pathophysiology of epilepsy, but underlying
mechanisms remain mostly unknown. Using immunohistochemistry for CD45 (common leukocyte antigen) and CD3 (T-lymphocytes),
we show here microglial activation and infiltration of leukocytes in sclerotic tissue from patients with mesial temporal lobe epilepsy
(TLE), as well as in a model of TLE (intrahippocampal kainic acid injection), characterized by spontaneous, nonconvulsive focal seizures.
Using specific markers of lymphocytes, microglia, macrophages, and neutrophils in kainate-treated mice, we investigated with pharmacological
and genetic approaches the contribution of innate and adaptive immunity to kainate-induced inflammation and neurodegeneration.
Furthermore, we used EEG analysis in mutant mice lacking specific subsets of lymphocytes to explore the significance of
inflammatory processes for epileptogenesis. Blood– brain barrier disruption and neurodegeneration in the kainate-lesioned hippocampus
were accompanied by sustained ICAM-1 upregulation, microglial cell activation, and infiltration of CD3+ T-cells. Moreover, macrophage
infiltration was observed, selectively in the dentate gyrus where prominent granule cell dispersion was evident. Unexpectedly,
depletion of peripheral macrophages by systemic clodronate liposome administration affected granule cell survival. Neurodegeneration
was aggravated in kainate-lesioned mice lacking T- and B-cells (RAG1-knock-out), because of delayed invasion by Gr-1+ neutrophils.
Most strikingly, these mutant mice exhibited early onset of spontaneous recurrent seizures, suggesting a strong impact of immunemediated
responses on network excitability. Together, the concerted action of adaptive and innate immunity triggered locally by intrahippocampal
kainate injection contributes seizure-suppressant and neuroprotective effects, shedding new light on neuroimmune
interactions in temporal lobe epilepsy.

Abstract

Clinical and experimental evidence indicates that inflammatory processes contribute to the pathophysiology of epilepsy, but underlying
mechanisms remain mostly unknown. Using immunohistochemistry for CD45 (common leukocyte antigen) and CD3 (T-lymphocytes),
we show here microglial activation and infiltration of leukocytes in sclerotic tissue from patients with mesial temporal lobe epilepsy
(TLE), as well as in a model of TLE (intrahippocampal kainic acid injection), characterized by spontaneous, nonconvulsive focal seizures.
Using specific markers of lymphocytes, microglia, macrophages, and neutrophils in kainate-treated mice, we investigated with pharmacological
and genetic approaches the contribution of innate and adaptive immunity to kainate-induced inflammation and neurodegeneration.
Furthermore, we used EEG analysis in mutant mice lacking specific subsets of lymphocytes to explore the significance of
inflammatory processes for epileptogenesis. Blood– brain barrier disruption and neurodegeneration in the kainate-lesioned hippocampus
were accompanied by sustained ICAM-1 upregulation, microglial cell activation, and infiltration of CD3+ T-cells. Moreover, macrophage
infiltration was observed, selectively in the dentate gyrus where prominent granule cell dispersion was evident. Unexpectedly,
depletion of peripheral macrophages by systemic clodronate liposome administration affected granule cell survival. Neurodegeneration
was aggravated in kainate-lesioned mice lacking T- and B-cells (RAG1-knock-out), because of delayed invasion by Gr-1+ neutrophils.
Most strikingly, these mutant mice exhibited early onset of spontaneous recurrent seizures, suggesting a strong impact of immunemediated
responses on network excitability. Together, the concerted action of adaptive and innate immunity triggered locally by intrahippocampal
kainate injection contributes seizure-suppressant and neuroprotective effects, shedding new light on neuroimmune
interactions in temporal lobe epilepsy.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2011
Deposited On:09 Jun 2011 14:59
Last Modified:26 Jan 2017 08:49
Publisher:Society for Neuroscience
ISSN:0270-6474
Publisher DOI:https://doi.org/10.1523/JNEUROSCI.6210-10.2011
Related URLs:https://www.zora.uzh.ch/48334/
PubMed ID:21411646

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