Reactive pericytes in early phase are involved in glial activation and late-onset hypersusceptibility to pilocarpine-induced seizures in traumatic brain injury model mice

Sakai, Kenta; Takata, Fuyuko; Yamanaka, Gaku; Yasunaga, Miho; Hashiguchi, Kana; Tominaga, Kazuki; Itoh, Kouichi; Kataoka, Yasufumi; Yamauchi, Atsushi; Dohgu, Shinya

doi:10.1016/j.jphs.2020.11.008

Cited by 14 publications

(10 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We should indicate that although neocortical changes in GABA and glutamatergic excitability can play a role in brain wide changes in functional connectivity in TBI, mechanisms involved in neurovascular coupling are also likely important (Ahmad et al ., 2012; Sakai et al ., 2021; Wu et al ., 2021). Loss of synchrony in BOLD could reflect underlying changes in neurovascular coupling, particularly with the occurrence of gliosis and astrocytic changes in the injury epicenter.…”

Section: Discussionmentioning

confidence: 99%

Compensatory functional connectome changes in a rat model of traumatic brain injury

Yang

Zhu

Pompilus

et al. 2021

Preprint

View full text Add to dashboard Cite

Penetrating cortical impact injuries alter neuronal communication beyond the injury epicenter, across regions involved in affective, sensorimotor, and cognitive processing. Understanding how traumatic brain injury (TBI) reorganizes local and brain wide nodal functional interactions may provide valuable quantitative parameters for monitoring pathological progression and functional recovery. To this end, we investigated spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal obtained at 11.1 Tesla in rats sustaining controlled cortical impact (CCI) and imaged at 2- and 30-days post-injury. Graph theory-based calculations were applied to weighted undirected matrices constructed from 12,879 pairwise correlations between fMRI signals from 162 regions. Our data indicate that on days 2 and 30 post-CCI there is a significant increase in connectivity strength in nodes located in contralesional cortical, thalamic, and basal forebrain areas. Rats imaged on day 2 post-injury had significantly greater network modularity than controls, with influential nodes (with high eigenvector centrality) contained within the contralesional module and participating less in cross-modular interactions. By day 30, modularity and cross-modular interactions recover, although a cluster of nodes with low strength and low eigenvector centrality remain in the ipsilateral cortex. Our results suggest that changes in node strength, modularity, eigenvector centrality, and participation coefficient track early and late TBI effects on brain functional connectivity. We propose that the observed compensatory functional connectivity reorganization in response to CCI may be unfavorable to brain wide communication in the early post-injury period.

show abstract

Section: Discussionmentioning

confidence: 99%

Compensatory functional connectome changes in a rat model of traumatic brain injury

Yang

Zhu

Pompilus

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…TNF-α-sensitive pericytes evoked microglial activation accompanied by increased iNOS through cooperation between the IκB-nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and Janus-activated kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathways ( Matsumoto et al, 2018 ). In TBI mice, an injury-induced pericyte response characterized by rapidly increased platelet-derived growth factor receptor β (PDGFRβ) expression was observed, followed by activation of microglia ( Sakai et al, 2021 ). Inhibition of PDGFRβ signaling in reactive pericytes in TBI mice suppressed the microglial activation, raising the possibility that the response of pericytes to pathological insults mediates the process of brain inflammation including microglial activation ( Sakai et al, 2021 ).…”

Section: Communications Between Bmecs and Other Cell Types In Neurovascular Units Leading To Bbb Dysfunctionmentioning

confidence: 99%

Blood-Brain Barrier Dysfunction Amplifies the Development of Neuroinflammation: Understanding of Cellular Events in Brain Microvascular Endothelial Cells for Prevention and Treatment of BBB Dysfunction

Takata

Nakagawa

Matsumoto

et al. 2021

Front. Cell. Neurosci.

Self Cite

266

142

View full text Add to dashboard Cite

Neuroinflammation is involved in the onset or progression of various neurodegenerative diseases. Initiation of neuroinflammation is triggered by endogenous substances (damage-associated molecular patterns) and/or exogenous pathogens. Activation of glial cells (microglia and astrocytes) is widely recognized as a hallmark of neuroinflammation and triggers the release of proinflammatory cytokines, leading to neurotoxicity and neuronal dysfunction. Another feature associated with neuroinflammatory diseases is impairment of the blood-brain barrier (BBB). The BBB, which is composed of brain endothelial cells connected by tight junctions, maintains brain homeostasis and protects neurons. Impairment of this barrier allows trafficking of immune cells or plasma proteins into the brain parenchyma and subsequent inflammatory processes in the brain. Besides neurons, activated glial cells also affect BBB integrity. Therefore, BBB dysfunction can amplify neuroinflammation and act as a key process in the development of neuroinflammation. BBB integrity is determined by the integration of multiple signaling pathways within brain endothelial cells through intercellular communication between brain endothelial cells and brain perivascular cells (pericytes, astrocytes, microglia, and oligodendrocytes). For prevention of BBB disruption, both cellular components, such as signaling molecules in brain endothelial cells, and non-cellular components, such as inflammatory mediators released by perivascular cells, should be considered. Thus, understanding of intracellular signaling pathways that disrupt the BBB can provide novel treatments for neurological diseases associated with neuroinflammation. In this review, we discuss current knowledge regarding the underlying mechanisms involved in BBB impairment by inflammatory mediators released by perivascular cells.

show abstract

“…Moreover, our recent studies found that pericytes may act as sensors for the inflammatory response in the CNS, as they react more intensely to TNF-a and proinflammatory cytokines than other cell types (e.g., brain endothelial cells or microglia), and release MMP-9 (impairing BBB function) and IL-6 (activating microglia) [ 81 , 106 , 110 , 111 ]. Recent experiences highlight the substantive role of pericytes in the pathogenesis of epilepsy [ 23 , 112 , 113 , 114 , 115 , 116 ]. Cerebrovascular pericytes undergo redistribution and remodeling, potentially contributing to BBB permeability, and inflammatory cytokines including IL-1β, TNFα, and IL-6 are deeply involved in the pathogenesis of pericyte-mediated epilepsy [ 117 ].…”

Section: Reviewmentioning

confidence: 99%

“…Based on these data, the possibility that brain pericytes act as sensors of inflammatory stimuli and effectors of inflammatory stimuli through MMP-9 and IL-8 release, and therefore have a role in peripheral immune cell transmigration to the brain parenchyma and seizure development, should be considered. In fact, pericyte regulation leads to seizure suppression, as demonstrated in vivo [ 115 ] and in vitro [ 116 ].…”

Section: Reviewmentioning

confidence: 99%

See 1 more Smart Citation

Links between Immune Cells from the Periphery and the Brain in the Pathogenesis of Epilepsy: A Narrative Review

Yamanaka

Morıchı

Takamatsu

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

Accumulating evidence has demonstrated that the pathogenesis of epilepsy is linked to neuroinflammation and cerebrovascular dysfunction. Peripheral immune cell invasion into the brain, along with these responses, is implicitly involved in epilepsy. This review explored the current literature on the association between the peripheral and central nervous systems in the pathogenesis of epilepsy, and highlights novel research directions for therapeutic interventions targeting these reactions. Previous experimental and human studies have demonstrated the activation of the innate and adaptive immune responses in the brain. The time required for monocytes (responsible for innate immunity) and T cells (involved in acquired immunity) to invade the central nervous system after a seizure varies. Moreover, the time between the leakage associated with blood–brain barrier (BBB) failure and the infiltration of these cells varies. This suggests that cell infiltration is not merely a secondary disruptive event associated with BBB failure, but also a non-disruptive event facilitated by various mediators produced by the neurovascular unit consisting of neurons, perivascular astrocytes, microglia, pericytes, and endothelial cells. Moreover, genetic manipulation has enabled the differentiation between peripheral monocytes and resident microglia, which was previously considered difficult. Thus, the evidence suggests that peripheral monocytes may contribute to the pathogenesis of seizures.

show abstract

Reactive pericytes in early phase are involved in glial activation and late-onset hypersusceptibility to pilocarpine-induced seizures in traumatic brain injury model mice

Cited by 14 publications

References 47 publications

Compensatory functional connectome changes in a rat model of traumatic brain injury

Compensatory functional connectome changes in a rat model of traumatic brain injury

Blood-Brain Barrier Dysfunction Amplifies the Development of Neuroinflammation: Understanding of Cellular Events in Brain Microvascular Endothelial Cells for Prevention and Treatment of BBB Dysfunction

Links between Immune Cells from the Periphery and the Brain in the Pathogenesis of Epilepsy: A Narrative Review

Contact Info

Product

Resources

About