Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification
Aims: Microglia survey the brain environment by sensing alarm signals to provide the first line of defense against injury or infection after which they acquire an activated phenotype, but they also respond to chemical signals sent from brain mast cells, sentinels of the immune system, when these are...
| Autores: | , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Sevilla (US) |
| Repositorio: | idUS. Depósito de Investigación de la Universidad de Sevilla |
| OAI Identifier: | oai:idus.us.es:11441/149455 |
| Acceso en línea: | https://hdl.handle.net/11441/149455 https://doi.org/10.1016/j.lfs.2023.121537 |
| Access Level: | acceso abierto |
| Palabra clave: | Microglia Acidification Calcium signaling Exocytosis Ketotifen Secretory vesicles Neuroinflammation |
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Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidificationRamírez-Ponce, M. PilarFlores Cordero, Juan AntonioBarrella, LorenzoAlés González de la Higuera, Eva MaríaMicrogliaAcidificationCalcium signalingExocytosisKetotifenSecretory vesiclesNeuroinflammationAims: Microglia survey the brain environment by sensing alarm signals to provide the first line of defense against injury or infection after which they acquire an activated phenotype, but they also respond to chemical signals sent from brain mast cells, sentinels of the immune system, when these are degranulated in response to noxious agents. Nevertheless, excessive microglia activation damages the surrounding healthy neural tissue causing progressive loss of neurons and inducing chronic inflammation. Thus, it would be of intense interest the development and application of agents which prevent mast cell mediator release and inhibit the actions of such mediators once released on microglia. Main methods: Fluorescence measurements of fura-2 and quinacrine were used to measure intracellular Ca2+ signaling and exocytotic vesicle fusion in resting and activated microglia. Key findings: We show that treatment of microglia with a cocktail of mast cell mediators induces microglia activation, phagocytosis, and exocytosis, and reveal by the first-time microglia undergo a phase of vesicular acidification just before the exocytotic fusion occurs. This acidification is an important process for vesicular maturation and contributes with ~25 % to the content that the vesicle can store and later release by exocytosis. Pre-incubation with ketotifen, a mast cell stabilizer and H1R antagonist completely abolished histaminemediated calcium signaling and acidification of microglial organelles, and concomitantly reduced the discharge of vesicle contents. Significance: These results highlight a key role for vesicle acidification in microglial physiology and provide a potential therapeutic target for diseases related to mast cell and microglia-mediated neuroinflammation.ElsevierFisiología Médica y BiofísicaBioquímica Médica y Biología Molecular e InmunologíaJunta de Andalucía2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/149455https://doi.org/10.1016/j.lfs.2023.121537reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésLIFE SCIENCES, 319.BIO-236https://www.sciencedirect.com/science/article/pii/S0024320523001716?via%3Dihubinfo:eu-repo/semantics/openAccessoai:idus.us.es:11441/1494552026-06-17T12:51:07Z |
| dc.title.none.fl_str_mv |
Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification |
| title |
Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification |
| spellingShingle |
Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification Ramírez-Ponce, M. Pilar Microglia Acidification Calcium signaling Exocytosis Ketotifen Secretory vesicles Neuroinflammation |
| title_short |
Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification |
| title_full |
Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification |
| title_fullStr |
Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification |
| title_full_unstemmed |
Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification |
| title_sort |
Ketotifen is a microglial stabilizer by inhibiting secretory vesicle acidification |
| dc.creator.none.fl_str_mv |
Ramírez-Ponce, M. Pilar Flores Cordero, Juan Antonio Barrella, Lorenzo Alés González de la Higuera, Eva María |
| author |
Ramírez-Ponce, M. Pilar |
| author_facet |
Ramírez-Ponce, M. Pilar Flores Cordero, Juan Antonio Barrella, Lorenzo Alés González de la Higuera, Eva María |
| author_role |
author |
| author2 |
Flores Cordero, Juan Antonio Barrella, Lorenzo Alés González de la Higuera, Eva María |
| author2_role |
author author author |
| dc.contributor.none.fl_str_mv |
Fisiología Médica y Biofísica Bioquímica Médica y Biología Molecular e Inmunología Junta de Andalucía |
| dc.subject.none.fl_str_mv |
Microglia Acidification Calcium signaling Exocytosis Ketotifen Secretory vesicles Neuroinflammation |
| topic |
Microglia Acidification Calcium signaling Exocytosis Ketotifen Secretory vesicles Neuroinflammation |
| description |
Aims: Microglia survey the brain environment by sensing alarm signals to provide the first line of defense against injury or infection after which they acquire an activated phenotype, but they also respond to chemical signals sent from brain mast cells, sentinels of the immune system, when these are degranulated in response to noxious agents. Nevertheless, excessive microglia activation damages the surrounding healthy neural tissue causing progressive loss of neurons and inducing chronic inflammation. Thus, it would be of intense interest the development and application of agents which prevent mast cell mediator release and inhibit the actions of such mediators once released on microglia. Main methods: Fluorescence measurements of fura-2 and quinacrine were used to measure intracellular Ca2+ signaling and exocytotic vesicle fusion in resting and activated microglia. Key findings: We show that treatment of microglia with a cocktail of mast cell mediators induces microglia activation, phagocytosis, and exocytosis, and reveal by the first-time microglia undergo a phase of vesicular acidification just before the exocytotic fusion occurs. This acidification is an important process for vesicular maturation and contributes with ~25 % to the content that the vesicle can store and later release by exocytosis. Pre-incubation with ketotifen, a mast cell stabilizer and H1R antagonist completely abolished histaminemediated calcium signaling and acidification of microglial organelles, and concomitantly reduced the discharge of vesicle contents. Significance: These results highlight a key role for vesicle acidification in microglial physiology and provide a potential therapeutic target for diseases related to mast cell and microglia-mediated neuroinflammation. |
| publishDate |
2023 |
| dc.date.none.fl_str_mv |
2023 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/11441/149455 https://doi.org/10.1016/j.lfs.2023.121537 |
| url |
https://hdl.handle.net/11441/149455 https://doi.org/10.1016/j.lfs.2023.121537 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
LIFE SCIENCES, 319. BIO-236 https://www.sciencedirect.com/science/article/pii/S0024320523001716?via%3Dihub |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
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Elsevier |
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reponame:idUS. Depósito de Investigación de la Universidad de Sevilla instname:Universidad de Sevilla (US) |
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Universidad de Sevilla (US) |
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idUS. Depósito de Investigación de la Universidad de Sevilla |
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idUS. Depósito de Investigación de la Universidad de Sevilla |
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