AIM2 deletion enhances blood‐brain barrier integrity in experimental ischemic stroke
Aims Ischemic stroke is a life‐threatening disease with limited therapeutic strategies. Blood‐brain barrier (BBB) disruption is a critical pathological process that contributes to poor outcomes in ischemic stroke. We previously showed that the microglial inhibition of the inflammasome sensor absent...
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| Veröffentlicht in: | CNS neuroscience & therapeutics 2021-10, Vol.27 (10), p.1224-1237 |
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| creator | Xu, Si‐yi Bian, Hui‐jie Shu, Shu Xia, Sheng‐nan Gu, Yue Zhang, Mei‐juan Xu, Yun Cao, Xiang |
| description | Aims
Ischemic stroke is a life‐threatening disease with limited therapeutic strategies. Blood‐brain barrier (BBB) disruption is a critical pathological process that contributes to poor outcomes in ischemic stroke. We previously showed that the microglial inhibition of the inflammasome sensor absent in melanoma 2 (AIM2) suppressed the inflammatory response and protected against ischemic stroke. However, whether AIM2 is involved in BBB disruption during cerebral ischemia is unknown.
Methods
Middle cerebral artery occlusion (MCAO) and oxygen‐glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice and brain microvascular endothelial cells (HBMECs), respectively. The infarct volume, neurological deficits, and BBB permeability were measured in mice after MCAO. Transendothelial electrical resistance (TEER) and neutrophil adhesion to the HBMEC monolayer were assessed after OGD/R treatment. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins.
Results
AIM2 was shown to be expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. AIM2 deletion reduced the infarct volume, improved neurological and motor functions, and decreased BBB disruption. In vitro, OGD/R significantly increased the protein levels of AIM2 and ICAM‐1 and decreased those of the tight junction (TJ) proteins ZO‐1 and occludin. AIM2 knockdown effectively protected BBB integrity by promoting the expression of TJ proteins and decreasing ICAM‐1 expression and neutrophil adhesion. Mechanistically, AIM2 knockdown reversed the OGD/R‐induced increases in ICAM‐1 expression and STAT3 phosphorylation in brain endothelial cells. Furthermore, treatment with the p‐STAT3 inhibitor AG490 mitigated the effect of AIM2 on BBB breakdown.
Conclusion
Our findings indicated that inhibiting AIM2 preserved the BBB integrity after ischemic stroke, at least partially by modulating STAT3 activation and that AIM2 may be a promising therapeutic target for cerebral ischemic stroke.
AIM2 deletion in brain endothelial cells reversed ischemia‐induced BBB injury by suppressing ICAM‐1 expression and neutrophil adhesion in a STAT3 signaling‐ dependent manner. |
| doi_str_mv | 10.1111/cns.13699 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8446221</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2573170957</sourcerecordid><originalsourceid>FETCH-LOGICAL-c4439-e7ca05ecb20c0103837f3bcaf0b4931ec383df169fe356b75a7537b8695ef0cd3</originalsourceid><addsrcrecordid>eNp1kc1OGzEURq0KVCh00ReoRmLTLgL2-G-8qRRFUJCgXUC7tWzPHWI6sYM9KWTXR-AZeRIMgaithDe-so-OvqsPoQ8E75NyDlzI-4QKpd6gbSI5H3HF1MZ6pngLvcv5CmNRN6p5i7YoI1wQTrfRz_HJWV210MPgY6ggTE1wkCvbx9je_7mzyfhQWZOSh1T5MMBl8sOyTBXcziH5GYTB9JXPbgoz76o8pPgLdtFmZ_oM75_vHfTj6PBicjw6_f71ZDI-HTnGqBqBdAZzcLbGDhNMGyo7ap3psGWKEnDlpe2IUB1QLqzkRnIqbSMUhw67lu6gLyvvfGFn0LoSJplez0suk5Y6Gq___Ql-qi_jb90wJuqaFMGnZ0GK1wvIg56VVaDvTYC4yLrmjBFRCyELuvcfehUXKZT1CiUpkVjxR-rzinIp5pygW4chWD-2pUtb-qmtwn78O_2afKmnAAcr4Mb3sHzdpCffzlfKBxa6oO4</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2573170957</pqid></control><display><type>article</type><title>AIM2 deletion enhances blood‐brain barrier integrity in experimental ischemic stroke</title><source>MEDLINE</source><source>Wiley Journals</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Wiley Online Library Open Access</source><source>PubMed Central</source><creator>Xu, Si‐yi ; Bian, Hui‐jie ; Shu, Shu ; Xia, Sheng‐nan ; Gu, Yue ; Zhang, Mei‐juan ; Xu, Yun ; Cao, Xiang</creator><creatorcontrib>Xu, Si‐yi ; Bian, Hui‐jie ; Shu, Shu ; Xia, Sheng‐nan ; Gu, Yue ; Zhang, Mei‐juan ; Xu, Yun ; Cao, Xiang</creatorcontrib><description>Aims
Ischemic stroke is a life‐threatening disease with limited therapeutic strategies. Blood‐brain barrier (BBB) disruption is a critical pathological process that contributes to poor outcomes in ischemic stroke. We previously showed that the microglial inhibition of the inflammasome sensor absent in melanoma 2 (AIM2) suppressed the inflammatory response and protected against ischemic stroke. However, whether AIM2 is involved in BBB disruption during cerebral ischemia is unknown.
Methods
Middle cerebral artery occlusion (MCAO) and oxygen‐glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice and brain microvascular endothelial cells (HBMECs), respectively. The infarct volume, neurological deficits, and BBB permeability were measured in mice after MCAO. Transendothelial electrical resistance (TEER) and neutrophil adhesion to the HBMEC monolayer were assessed after OGD/R treatment. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins.
Results
AIM2 was shown to be expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. AIM2 deletion reduced the infarct volume, improved neurological and motor functions, and decreased BBB disruption. In vitro, OGD/R significantly increased the protein levels of AIM2 and ICAM‐1 and decreased those of the tight junction (TJ) proteins ZO‐1 and occludin. AIM2 knockdown effectively protected BBB integrity by promoting the expression of TJ proteins and decreasing ICAM‐1 expression and neutrophil adhesion. Mechanistically, AIM2 knockdown reversed the OGD/R‐induced increases in ICAM‐1 expression and STAT3 phosphorylation in brain endothelial cells. Furthermore, treatment with the p‐STAT3 inhibitor AG490 mitigated the effect of AIM2 on BBB breakdown.
Conclusion
Our findings indicated that inhibiting AIM2 preserved the BBB integrity after ischemic stroke, at least partially by modulating STAT3 activation and that AIM2 may be a promising therapeutic target for cerebral ischemic stroke.
AIM2 deletion in brain endothelial cells reversed ischemia‐induced BBB injury by suppressing ICAM‐1 expression and neutrophil adhesion in a STAT3 signaling‐ dependent manner.</description><identifier>ISSN: 1755-5930</identifier><identifier>EISSN: 1755-5949</identifier><identifier>DOI: 10.1111/cns.13699</identifier><identifier>PMID: 34156153</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>AIM2 ; Animals ; Blood-brain barrier ; Blood-Brain Barrier - pathology ; Brain research ; Cerebral blood flow ; DNA-Binding Proteins - genetics ; Electric Impedance ; Electrical resistivity ; Endothelial Cells ; Glucose ; Glucose - deficiency ; Hypoxia - pathology ; Immunofluorescence ; Infarction, Middle Cerebral Artery - pathology ; Inflammasomes ; Inflammation ; Intercellular Adhesion Molecule-1 - genetics ; Ischemia ; ischemic stroke ; Ischemic Stroke - genetics ; Ischemic Stroke - pathology ; Leukocytes (neutrophilic) ; Male ; Melanoma ; Membrane permeability ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microvasculature ; Nervous System Diseases - etiology ; Nervous System Diseases - physiopathology ; Neurological diseases ; Original ; Permeability ; Phosphorylation ; Proteins ; Reperfusion Injury - pathology ; STAT3 ; Stat3 protein ; STAT3 Transcription Factor - genetics ; Stroke ; Therapeutic targets ; Up-Regulation - genetics ; Veins & arteries</subject><ispartof>CNS neuroscience & therapeutics, 2021-10, Vol.27 (10), p.1224-1237</ispartof><rights>2021 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4439-e7ca05ecb20c0103837f3bcaf0b4931ec383df169fe356b75a7537b8695ef0cd3</citedby><cites>FETCH-LOGICAL-c4439-e7ca05ecb20c0103837f3bcaf0b4931ec383df169fe356b75a7537b8695ef0cd3</cites><orcidid>0000-0001-5288-0319 ; 0000-0002-4573-8741</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446221/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8446221/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34156153$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xu, Si‐yi</creatorcontrib><creatorcontrib>Bian, Hui‐jie</creatorcontrib><creatorcontrib>Shu, Shu</creatorcontrib><creatorcontrib>Xia, Sheng‐nan</creatorcontrib><creatorcontrib>Gu, Yue</creatorcontrib><creatorcontrib>Zhang, Mei‐juan</creatorcontrib><creatorcontrib>Xu, Yun</creatorcontrib><creatorcontrib>Cao, Xiang</creatorcontrib><title>AIM2 deletion enhances blood‐brain barrier integrity in experimental ischemic stroke</title><title>CNS neuroscience & therapeutics</title><addtitle>CNS Neurosci Ther</addtitle><description>Aims
Ischemic stroke is a life‐threatening disease with limited therapeutic strategies. Blood‐brain barrier (BBB) disruption is a critical pathological process that contributes to poor outcomes in ischemic stroke. We previously showed that the microglial inhibition of the inflammasome sensor absent in melanoma 2 (AIM2) suppressed the inflammatory response and protected against ischemic stroke. However, whether AIM2 is involved in BBB disruption during cerebral ischemia is unknown.
Methods
Middle cerebral artery occlusion (MCAO) and oxygen‐glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice and brain microvascular endothelial cells (HBMECs), respectively. The infarct volume, neurological deficits, and BBB permeability were measured in mice after MCAO. Transendothelial electrical resistance (TEER) and neutrophil adhesion to the HBMEC monolayer were assessed after OGD/R treatment. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins.
Results
AIM2 was shown to be expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. AIM2 deletion reduced the infarct volume, improved neurological and motor functions, and decreased BBB disruption. In vitro, OGD/R significantly increased the protein levels of AIM2 and ICAM‐1 and decreased those of the tight junction (TJ) proteins ZO‐1 and occludin. AIM2 knockdown effectively protected BBB integrity by promoting the expression of TJ proteins and decreasing ICAM‐1 expression and neutrophil adhesion. Mechanistically, AIM2 knockdown reversed the OGD/R‐induced increases in ICAM‐1 expression and STAT3 phosphorylation in brain endothelial cells. Furthermore, treatment with the p‐STAT3 inhibitor AG490 mitigated the effect of AIM2 on BBB breakdown.
Conclusion
Our findings indicated that inhibiting AIM2 preserved the BBB integrity after ischemic stroke, at least partially by modulating STAT3 activation and that AIM2 may be a promising therapeutic target for cerebral ischemic stroke.
AIM2 deletion in brain endothelial cells reversed ischemia‐induced BBB injury by suppressing ICAM‐1 expression and neutrophil adhesion in a STAT3 signaling‐ dependent manner.</description><subject>AIM2</subject><subject>Animals</subject><subject>Blood-brain barrier</subject><subject>Blood-Brain Barrier - pathology</subject><subject>Brain research</subject><subject>Cerebral blood flow</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Electric Impedance</subject><subject>Electrical resistivity</subject><subject>Endothelial Cells</subject><subject>Glucose</subject><subject>Glucose - deficiency</subject><subject>Hypoxia - pathology</subject><subject>Immunofluorescence</subject><subject>Infarction, Middle Cerebral Artery - pathology</subject><subject>Inflammasomes</subject><subject>Inflammation</subject><subject>Intercellular Adhesion Molecule-1 - genetics</subject><subject>Ischemia</subject><subject>ischemic stroke</subject><subject>Ischemic Stroke - genetics</subject><subject>Ischemic Stroke - pathology</subject><subject>Leukocytes (neutrophilic)</subject><subject>Male</subject><subject>Melanoma</subject><subject>Membrane permeability</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Microvasculature</subject><subject>Nervous System Diseases - etiology</subject><subject>Nervous System Diseases - physiopathology</subject><subject>Neurological diseases</subject><subject>Original</subject><subject>Permeability</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Reperfusion Injury - pathology</subject><subject>STAT3</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>Stroke</subject><subject>Therapeutic targets</subject><subject>Up-Regulation - genetics</subject><subject>Veins & arteries</subject><issn>1755-5930</issn><issn>1755-5949</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kc1OGzEURq0KVCh00ReoRmLTLgL2-G-8qRRFUJCgXUC7tWzPHWI6sYM9KWTXR-AZeRIMgaithDe-so-OvqsPoQ8E75NyDlzI-4QKpd6gbSI5H3HF1MZ6pngLvcv5CmNRN6p5i7YoI1wQTrfRz_HJWV210MPgY6ggTE1wkCvbx9je_7mzyfhQWZOSh1T5MMBl8sOyTBXcziH5GYTB9JXPbgoz76o8pPgLdtFmZ_oM75_vHfTj6PBicjw6_f71ZDI-HTnGqBqBdAZzcLbGDhNMGyo7ap3psGWKEnDlpe2IUB1QLqzkRnIqbSMUhw67lu6gLyvvfGFn0LoSJplez0suk5Y6Gq___Ql-qi_jb90wJuqaFMGnZ0GK1wvIg56VVaDvTYC4yLrmjBFRCyELuvcfehUXKZT1CiUpkVjxR-rzinIp5pygW4chWD-2pUtb-qmtwn78O_2afKmnAAcr4Mb3sHzdpCffzlfKBxa6oO4</recordid><startdate>202110</startdate><enddate>202110</enddate><creator>Xu, Si‐yi</creator><creator>Bian, Hui‐jie</creator><creator>Shu, Shu</creator><creator>Xia, Sheng‐nan</creator><creator>Gu, Yue</creator><creator>Zhang, Mei‐juan</creator><creator>Xu, Yun</creator><creator>Cao, Xiang</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5288-0319</orcidid><orcidid>https://orcid.org/0000-0002-4573-8741</orcidid></search><sort><creationdate>202110</creationdate><title>AIM2 deletion enhances blood‐brain barrier integrity in experimental ischemic stroke</title><author>Xu, Si‐yi ; Bian, Hui‐jie ; Shu, Shu ; Xia, Sheng‐nan ; Gu, Yue ; Zhang, Mei‐juan ; Xu, Yun ; Cao, Xiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4439-e7ca05ecb20c0103837f3bcaf0b4931ec383df169fe356b75a7537b8695ef0cd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>AIM2</topic><topic>Animals</topic><topic>Blood-brain barrier</topic><topic>Blood-Brain Barrier - pathology</topic><topic>Brain research</topic><topic>Cerebral blood flow</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Electric Impedance</topic><topic>Electrical resistivity</topic><topic>Endothelial Cells</topic><topic>Glucose</topic><topic>Glucose - deficiency</topic><topic>Hypoxia - pathology</topic><topic>Immunofluorescence</topic><topic>Infarction, Middle Cerebral Artery - pathology</topic><topic>Inflammasomes</topic><topic>Inflammation</topic><topic>Intercellular Adhesion Molecule-1 - genetics</topic><topic>Ischemia</topic><topic>ischemic stroke</topic><topic>Ischemic Stroke - genetics</topic><topic>Ischemic Stroke - pathology</topic><topic>Leukocytes (neutrophilic)</topic><topic>Male</topic><topic>Melanoma</topic><topic>Membrane permeability</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Microvasculature</topic><topic>Nervous System Diseases - etiology</topic><topic>Nervous System Diseases - physiopathology</topic><topic>Neurological diseases</topic><topic>Original</topic><topic>Permeability</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Reperfusion Injury - pathology</topic><topic>STAT3</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - genetics</topic><topic>Stroke</topic><topic>Therapeutic targets</topic><topic>Up-Regulation - genetics</topic><topic>Veins & arteries</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Xu, Si‐yi</creatorcontrib><creatorcontrib>Bian, Hui‐jie</creatorcontrib><creatorcontrib>Shu, Shu</creatorcontrib><creatorcontrib>Xia, Sheng‐nan</creatorcontrib><creatorcontrib>Gu, Yue</creatorcontrib><creatorcontrib>Zhang, Mei‐juan</creatorcontrib><creatorcontrib>Xu, Yun</creatorcontrib><creatorcontrib>Cao, Xiang</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Online Library (Open Access Collection)</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>CNS neuroscience & therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Xu, Si‐yi</au><au>Bian, Hui‐jie</au><au>Shu, Shu</au><au>Xia, Sheng‐nan</au><au>Gu, Yue</au><au>Zhang, Mei‐juan</au><au>Xu, Yun</au><au>Cao, Xiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>AIM2 deletion enhances blood‐brain barrier integrity in experimental ischemic stroke</atitle><jtitle>CNS neuroscience & therapeutics</jtitle><addtitle>CNS Neurosci Ther</addtitle><date>2021-10</date><risdate>2021</risdate><volume>27</volume><issue>10</issue><spage>1224</spage><epage>1237</epage><pages>1224-1237</pages><issn>1755-5930</issn><eissn>1755-5949</eissn><abstract>Aims
Ischemic stroke is a life‐threatening disease with limited therapeutic strategies. Blood‐brain barrier (BBB) disruption is a critical pathological process that contributes to poor outcomes in ischemic stroke. We previously showed that the microglial inhibition of the inflammasome sensor absent in melanoma 2 (AIM2) suppressed the inflammatory response and protected against ischemic stroke. However, whether AIM2 is involved in BBB disruption during cerebral ischemia is unknown.
Methods
Middle cerebral artery occlusion (MCAO) and oxygen‐glucose deprivation/reoxygenation (OGD/R) were used to mimic cerebral ischemia in mice and brain microvascular endothelial cells (HBMECs), respectively. The infarct volume, neurological deficits, and BBB permeability were measured in mice after MCAO. Transendothelial electrical resistance (TEER) and neutrophil adhesion to the HBMEC monolayer were assessed after OGD/R treatment. Western blot and immunofluorescence analyses were conducted to evaluate the expression of related proteins.
Results
AIM2 was shown to be expressed in brain endothelial cells and upregulated after ischemic stroke in the mouse brain. AIM2 deletion reduced the infarct volume, improved neurological and motor functions, and decreased BBB disruption. In vitro, OGD/R significantly increased the protein levels of AIM2 and ICAM‐1 and decreased those of the tight junction (TJ) proteins ZO‐1 and occludin. AIM2 knockdown effectively protected BBB integrity by promoting the expression of TJ proteins and decreasing ICAM‐1 expression and neutrophil adhesion. Mechanistically, AIM2 knockdown reversed the OGD/R‐induced increases in ICAM‐1 expression and STAT3 phosphorylation in brain endothelial cells. Furthermore, treatment with the p‐STAT3 inhibitor AG490 mitigated the effect of AIM2 on BBB breakdown.
Conclusion
Our findings indicated that inhibiting AIM2 preserved the BBB integrity after ischemic stroke, at least partially by modulating STAT3 activation and that AIM2 may be a promising therapeutic target for cerebral ischemic stroke.
AIM2 deletion in brain endothelial cells reversed ischemia‐induced BBB injury by suppressing ICAM‐1 expression and neutrophil adhesion in a STAT3 signaling‐ dependent manner.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>34156153</pmid><doi>10.1111/cns.13699</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0001-5288-0319</orcidid><orcidid>https://orcid.org/0000-0002-4573-8741</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | AIM2 Animals Blood-brain barrier Blood-Brain Barrier - pathology Brain research Cerebral blood flow DNA-Binding Proteins - genetics Electric Impedance Electrical resistivity Endothelial Cells Glucose Glucose - deficiency Hypoxia - pathology Immunofluorescence Infarction, Middle Cerebral Artery - pathology Inflammasomes Inflammation Intercellular Adhesion Molecule-1 - genetics Ischemia ischemic stroke Ischemic Stroke - genetics Ischemic Stroke - pathology Leukocytes (neutrophilic) Male Melanoma Membrane permeability Mice Mice, Inbred C57BL Mice, Knockout Microvasculature Nervous System Diseases - etiology Nervous System Diseases - physiopathology Neurological diseases Original Permeability Phosphorylation Proteins Reperfusion Injury - pathology STAT3 Stat3 protein STAT3 Transcription Factor - genetics Stroke Therapeutic targets Up-Regulation - genetics Veins & arteries |
| title | AIM2 deletion enhances blood‐brain barrier integrity in experimental ischemic stroke |
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