P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis
Abstract Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen‐ or tissue damage‐induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative r...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2018-08-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201708743 |
| _version_ | 1797288100711366656 |
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| author | Alazne Zabala Nuria Vazquez‐Villoldo Björn Rissiek Jon Gejo Abraham Martin Aitor Palomino Alberto Perez‐Samartín Krishna R Pulagam Marco Lukowiak Estibaliz Capetillo‐Zarate Jordi Llop Tim Magnus Friedrich Koch‐Nolte Francois Rassendren Carlos Matute María Domercq |
| author_facet | Alazne Zabala Nuria Vazquez‐Villoldo Björn Rissiek Jon Gejo Abraham Martin Aitor Palomino Alberto Perez‐Samartín Krishna R Pulagam Marco Lukowiak Estibaliz Capetillo‐Zarate Jordi Llop Tim Magnus Friedrich Koch‐Nolte Francois Rassendren Carlos Matute María Domercq |
| author_sort | Alazne Zabala |
| collection | DOAJ |
| description | Abstract Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen‐ or tissue damage‐induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative responses. Here, we analyzed the role of purinergic receptor P2X4 (P2X4R) in microglia/macrophages during autoimmune inflammation. Blockade of P2X4R signaling exacerbated clinical signs in the experimental autoimmune encephalomyelitis (EAE) model and also favored microglia activation to a pro‐inflammatory phenotype and inhibited myelin phagocytosis. Moreover, P2X4R blockade in microglia halted oligodendrocyte differentiation in vitro and remyelination after lysolecithin‐induced demyelination. Conversely, potentiation of P2X4R signaling by the allosteric modulator ivermectin (IVM) favored a switch in microglia to an anti‐inflammatory phenotype, potentiated myelin phagocytosis, promoted the remyelination response, and ameliorated clinical signs of EAE. Our results provide evidence that P2X4Rs modulate microglia/macrophage inflammatory responses and identify IVM as a potential candidate among currently used drugs to promote the repair of myelin damage. |
| first_indexed | 2024-03-07T18:44:27Z |
| format | Article |
| id | doaj.art-6b036f57b38241f7aed0778adc3f902c |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T18:44:27Z |
| publishDate | 2018-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-6b036f57b38241f7aed0778adc3f902c2024-03-02T02:49:59ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842018-08-01108n/an/a10.15252/emmm.201708743P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitisAlazne Zabala0Nuria Vazquez‐Villoldo1Björn Rissiek2Jon Gejo3Abraham Martin4Aitor Palomino5Alberto Perez‐Samartín6Krishna R Pulagam7Marco Lukowiak8Estibaliz Capetillo‐Zarate9Jordi Llop10Tim Magnus11Friedrich Koch‐Nolte12Francois Rassendren13Carlos Matute14María Domercq15Achucarro Basque Center for Neurosciences CIBERNED and Departamento de Neurociencias Universidad del País Vasco Leioa SpainAchucarro Basque Center for Neurosciences CIBERNED and Departamento de Neurociencias Universidad del País Vasco Leioa SpainDepartment of Neurology University Medical Center Hamburg GermanyAchucarro Basque Center for Neurosciences CIBERNED and Departamento de Neurociencias Universidad del País Vasco Leioa SpainMolecular Imaging Unit CIC biomaGUNE San Sebastian SpainAchucarro Basque Center for Neurosciences CIBERNED and Departamento de Neurociencias Universidad del País Vasco Leioa SpainAchucarro Basque Center for Neurosciences CIBERNED and Departamento de Neurociencias Universidad del País Vasco Leioa SpainMolecular Imaging Unit CIC biomaGUNE San Sebastian SpainDepartment of Neurology University Medical Center Hamburg GermanyAchucarro Basque Center for Neurosciences CIBERNED and Departamento de Neurociencias Universidad del País Vasco Leioa SpainMolecular Imaging Unit CIC biomaGUNE San Sebastian SpainDepartment of Neurology University Medical Center Hamburg GermanyInstitute of Immunology University Medical Center Hamburg GermanyInstitut de Génomique Functionnelle CNRS UMR5203 Montpellier FranceAchucarro Basque Center for Neurosciences CIBERNED and Departamento de Neurociencias Universidad del País Vasco Leioa SpainAchucarro Basque Center for Neurosciences CIBERNED and Departamento de Neurociencias Universidad del País Vasco Leioa SpainAbstract Microglia survey the brain microenvironment for signals of injury or infection and are essential for the initiation and resolution of pathogen‐ or tissue damage‐induced inflammation. Understanding the mechanism of microglia responses during pathology is hence vital to promote regenerative responses. Here, we analyzed the role of purinergic receptor P2X4 (P2X4R) in microglia/macrophages during autoimmune inflammation. Blockade of P2X4R signaling exacerbated clinical signs in the experimental autoimmune encephalomyelitis (EAE) model and also favored microglia activation to a pro‐inflammatory phenotype and inhibited myelin phagocytosis. Moreover, P2X4R blockade in microglia halted oligodendrocyte differentiation in vitro and remyelination after lysolecithin‐induced demyelination. Conversely, potentiation of P2X4R signaling by the allosteric modulator ivermectin (IVM) favored a switch in microglia to an anti‐inflammatory phenotype, potentiated myelin phagocytosis, promoted the remyelination response, and ameliorated clinical signs of EAE. Our results provide evidence that P2X4Rs modulate microglia/macrophage inflammatory responses and identify IVM as a potential candidate among currently used drugs to promote the repair of myelin damage.https://doi.org/10.15252/emmm.201708743microgliamyelin phagocytosisP2X4 receptorremyelination |
| spellingShingle | Alazne Zabala Nuria Vazquez‐Villoldo Björn Rissiek Jon Gejo Abraham Martin Aitor Palomino Alberto Perez‐Samartín Krishna R Pulagam Marco Lukowiak Estibaliz Capetillo‐Zarate Jordi Llop Tim Magnus Friedrich Koch‐Nolte Francois Rassendren Carlos Matute María Domercq P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis EMBO Molecular Medicine microglia myelin phagocytosis P2X4 receptor remyelination |
| title | P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis |
| title_full | P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis |
| title_fullStr | P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis |
| title_full_unstemmed | P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis |
| title_short | P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis |
| title_sort | p2x4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis |
| topic | microglia myelin phagocytosis P2X4 receptor remyelination |
| url | https://doi.org/10.15252/emmm.201708743 |
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