TLR2-induced astrocyte MMP9 activation compromises the blood brain barrier and exacerbates intracerebral hemorrhage in animal models
Open accessAbstract
BACKGROUND: The innate immune response plays an important role in the pathogenesis of intracerebral hemorrhage (ICH). Recent studies have shown that Toll-like receptor 2 (TLR2) is involved in the innate immune response in various neurological diseases, yet neither its role in ICH nor the mechanisms by which it functions have yet been elucidated. We examined these in this study using a collagenase-induced mouse ICH model with TLR2 knock-out (KO) mice. RESULTS: TLR2 expression was upregulated in the ipsilateral hemorrhagic tissues of the collagenase-injected mice. Brain injury volume and neurological deficits following ICH were reduced in TLR2 KO mice compared to wild-type (WT) control mice. Heterologous blood-transfer experiments show that TLR2 signaling in brain-resident cells, but not leukocytes, contributes to the injury. In our study to elucidate underlying mechanisms, we found that damage to blood-brain barrier (BBB) integrity following ICH was attenuated in TLR2 KO mice compared to WT mice, which may be due to reduced matrix metalloproteinase-9 (MMP9) activation in astrocytes. The reduced BBB damage accompanies decreased neutrophil infiltration and proinflammatory gene expression in the injured brain parenchyma, which may account for the attenuated brain damage in TLR2 KO mice after ICH. CONCLUSIONS: TLR2 plays a detrimental role in ICH-induced brain damage by activating MMP9 in astrocytes, compromising BBB, and enhancing neutrophils infiltration and proinflammatory gene expression.
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Reactive astrocytes are a major source of various vascular permeability factors.
“Reactive astrocytes are a major source of various vascular permeability factors [44–47].”
From Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain (2022) · cites this paper as [47]
The Results (section ‘TLR2 stimulation induces MMP9 activation in brain astrocytes’; page unavailable) report that, after intracerebral hemorrhage in mice, MMP9 expression was primarily detected in astrocytes rather than macrophages or microglia. The Background links MMP activation to blood–brain barrier disruption, supporting astrocytes as a source of one permeability-related factor in this setting. The paper does not establish that reactive astrocytes are a major source of various such factors generally. (LLM, conf=0.86)
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- Authors
- Min, H., Hong, J., Cho, I.-H., Jang, Y. H., Lee, H., Kim, D., Yu, S.-W., Lee, S., & Lee, S. J.
- Affiliations
- Seoul National University (KR)
- Kyung Hee University (KR)
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- Corresponding author
- Lee, Soojin
- ORCID
- Venue
- Molecular Brain
- Published
- 2015-04-10
- Volume
- 8
- Issue
- 1
- Pages
- 23-23
- ISSN
- 1756-6606 (ISSN-L)
- PMC
- PMC4397689
- OpenAlex
- W2128440535
- Cited by
- 76
- References
- 55
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 5 · 2022: 12 · 2021: 13 · 2020: 9 · 2019: 10 · 2018: 6 · 2017: 6 · 2016: 2 · 2015: 1
- FWCI
- 3.52
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Molecular Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Research Foundation
- Ministry of Science, ICT and Future Planning (2013R1A1A2074231)
- National Research Foundation of Korea (2013R1A2A2A01067248, 2013R1A1A2074231)
- Topics
- Health Sciences › Medicine › Neurology › Intracerebral and Subarachnoid Hemorrhage Research
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Keywords
- intracerebral hemorrhage, TLR2, astrocytes, MMP-9, blood-brain barrier, innate immunity, collagenase-induced hemorrhage, TLR2 knockout mice, neutrophil infiltration, pro-inflammatory gene expression, brain injury
- MeSH terms
- Animals, Astrocytes, Blood-Brain Barrier, Cerebral Hemorrhage, Disease Models, Animal, Enzyme Activation, Mice, Inbred C57BL, Signal Transduction, Collagenases, Mice, Knockout, Disease Progression, Intercellular Adhesion Molecule-1, Chemokines, Neutrophil Infiltration, Matrix Metalloproteinase 9, Toll-Like Receptor 2
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