Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity
Abstract Background Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood–brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, t...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02908-5 |
| _version_ | 1797557644890734592 |
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| author | Julia Castillo-González José Luis Ruiz Ignacio Serrano-Martínez Irene Forte-Lago Ana Ubago-Rodriguez Marta Caro Jesús Miguel Pérez-Gómez Alejandro Benítez-Troncoso Eduardo Andrés-León Macarena Sánchez-Navarro Raúl M. Luque Elena González-Rey |
| author_facet | Julia Castillo-González José Luis Ruiz Ignacio Serrano-Martínez Irene Forte-Lago Ana Ubago-Rodriguez Marta Caro Jesús Miguel Pérez-Gómez Alejandro Benítez-Troncoso Eduardo Andrés-León Macarena Sánchez-Navarro Raúl M. Luque Elena González-Rey |
| author_sort | Julia Castillo-González |
| collection | DOAJ |
| description | Abstract Background Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood–brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment. Methods Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS. Results The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage. Conclusions The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB. |
| first_indexed | 2024-03-10T17:19:32Z |
| format | Article |
| id | doaj.art-b2caf9906f144b4b854abd568b8551c1 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-10T17:19:32Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-b2caf9906f144b4b854abd568b8551c12023-11-20T10:24:08ZengBMCJournal of Neuroinflammation1742-20942023-10-0120112510.1186/s12974-023-02908-5Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrityJulia Castillo-González0José Luis Ruiz1Ignacio Serrano-Martínez2Irene Forte-Lago3Ana Ubago-Rodriguez4Marta Caro5Jesús Miguel Pérez-Gómez6Alejandro Benítez-Troncoso7Eduardo Andrés-León8Macarena Sánchez-Navarro9Raúl M. Luque10Elena González-Rey11Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICInstitute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICInstitute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICInstitute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICInstitute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICInstitute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICMaimonides Biomedical Research Institute of Cordoba (IMIBIC)Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICInstitute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICInstitute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICMaimonides Biomedical Research Institute of Cordoba (IMIBIC)Institute of Parasitology and Biomedicine Lopez-Neyra (IPBLN), CSICAbstract Background Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood–brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment. Methods Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS. Results The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage. Conclusions The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB.https://doi.org/10.1186/s12974-023-02908-5Blood–brain barrierCortistatinTight-junctionsBrain endothelium transcriptomeOxygen–glucose deprivationIschemia |
| spellingShingle | Julia Castillo-González José Luis Ruiz Ignacio Serrano-Martínez Irene Forte-Lago Ana Ubago-Rodriguez Marta Caro Jesús Miguel Pérez-Gómez Alejandro Benítez-Troncoso Eduardo Andrés-León Macarena Sánchez-Navarro Raúl M. Luque Elena González-Rey Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity Journal of Neuroinflammation Blood–brain barrier Cortistatin Tight-junctions Brain endothelium transcriptome Oxygen–glucose deprivation Ischemia |
| title | Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity |
| title_full | Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity |
| title_fullStr | Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity |
| title_full_unstemmed | Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity |
| title_short | Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity |
| title_sort | cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways exacerbated immune activation and disrupted barrier integrity |
| topic | Blood–brain barrier Cortistatin Tight-junctions Brain endothelium transcriptome Oxygen–glucose deprivation Ischemia |
| url | https://doi.org/10.1186/s12974-023-02908-5 |
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