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Loss of Endothelial Laminin ?5 Exacerbates Hemorrhagic Brain Injury.

ABSTRACT: Endothelial cells make laminin-411 and laminin-511. Although laminin-411 is well studied, the role of laminin-511 remains largely unknown due to the embryonic lethality of lama5^-/- mutants. In this study, we generated endothelium-specific lama5 conditional knockout (?5-TKO) mice and investigated the biological functions of endothelial lama5 in blood-brain barrier (BBB) maintenance under homeostatic conditions and the pathogenesis of intracerebral hemorrhage (ICH). First, the BBB integrity of ?5-TKO mice was measured under homeostatic conditions. Next, ICH was induced in ?5-TKO mice and their littermate controls using the collagenase model. Various parameters, including injury volume, neuronal death, neurological score, brain edema, BBB integrity, inflammatory cell infiltration, and gliosis, were examined at various time points after injury. Under homeostatic conditions, comparable levels of IgG or exogenous tracers were detected in ?5-TKO and control mice. Additionally, no differences in tight junction expression, pericyte coverage, and astrocyte polarity were found in these mice. After ICH, ?5-TKO mice displayed enlarged injury volume, increased neuronal death, elevated BBB permeability, exacerbated infiltration of inflammatory cells (leukocytes, neutrophils, and mononuclear cells), aggravated gliosis, unchanged brain edema, and worse neurological function, compared to the controls. These findings suggest that endothelial lama5 is dispensable for BBB maintenance under homeostatic conditions but plays a beneficial role in ICH.

SUBMITTER: Gautam J

PROVIDER: S-EPMC6663661 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Loss of Endothelial Laminin α5 Exacerbates Hemorrhagic Brain Injury.

Gautam Jyoti J Miner Jeffrey H JH Yao Yao Y

Translational stroke research 20190129 6

Endothelial cells make laminin-411 and laminin-511. Although laminin-411 is well studied, the role of laminin-511 remains largely unknown due to the embryonic lethality of lama5<sup>-/-</sup> mutants. In this study, we generated endothelium-specific lama5 conditional knockout (α5-TKO) mice and investigated the biological functions of endothelial lama5 in blood-brain barrier (BBB) maintenance under homeostatic conditions and the pathogenesis of intracerebral hemorrhage (ICH). First, the BBB integ ...[more]

PMID: 30693425

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Project description:Streptococcus pneumoniae meningitis is a life-threatening bacterial infection of the central nervous system (CNS), and its unfavorable prognosis usually results from an intense inflammatory response. Recent studies have shown that brain-derived neurotrophic factor (BDNF) mediates anti-inflammatory and neuroprotective effects in CNS diseases; however, the distinct contribution of BDNF to pneumococcal meningitis (PM) remains unknown. In this study, we sought to investigate the effects of endogenous BDNF on the inflammatory response and brain damage in experimental PM. We used Camk2a-CreERT2 mice to delete Bdnf from the cerebral cortex and hippocampus, and meningitis was induced by intracisternal infection with S. pneumoniae. Clinical parameters were assessed during acute meningitis. At 24 h post-infection, histopathology, neutrophil granulocytes infiltration, and microglia/macrophage proliferation of brain tissues were evaluated. Additionally, cortical damage and hippocampal apoptosis were assessed using Nissl staining and terminal deoxynucleotidyl transferase dUTP-nick-end labeling (TUNEL), respectively. Pro-inflammatory cytokine levels were determined using real-time polymerase chain reaction (RT-PCR). Key molecules associated with the related signaling pathways were analyzed by RT-PCR and western blot. To investigate the role of microglia/macrophage in infected BDNF conditional knockout mice, GW2580 was used for microglia/macrophage depletion. Here, we, for the first time, found that BDNF conditional knockouts exhibited more profound clinical impairment, pathological severity, and neuron injury and enhanced microglia/macrophage proliferation than were observed in their littermate controls. Furthermore, the BDNF conditional knockouts showed an obviously increase in the expression of pro-inflammatory factors (Tnf-α, Il-1β, and Il-6). Mechanistically, loss of BDNF activated TLR2- and NOD2-mediated downstream nuclear factor kappa B (NF-κB) p65 and p38 mitogen-activated protein kinase (MAPK) pathways associated with S. pneumoniae infection. Furthermore, targeted depletion of microglia/macrophage population decreased the resistance of mice to PM with diminishing neuroinflammation in BDNF conditional knockouts. Our findings suggest that loss of BDNF may enhance the inflammatory response and contribute to brain injury during PM at least partially by modulating TLR2- and NOD2-mediated signaling pathways, thereby providing a potential therapeutic target for future interventions in bacterial meningitis pathologies.

Dataset Information

Loss of Endothelial Laminin ?5 Exacerbates Hemorrhagic Brain Injury.

Publications

Loss of Endothelial Laminin α5 Exacerbates Hemorrhagic Brain Injury.

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