Journal
EMBO MOLECULAR MEDICINE
Volume 10, Issue 8, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201708743
Keywords
microglia; myelin phagocytosis; P2X4 receptor; remyelination
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Funding
- Merck Serono (a business of Merck KGaA, Darmstadt, Germany)
- Spanish Ministry of Education and Science [SAF2013-45084-R, SAF2016-75292-R]
- Basque Government
- University of the Basque Country (UPV/EHU)
- Centro de Investigacion Biomedica en Red, Enfermedades Neurodegenerativas (CIBERNED)
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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 invitro 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.
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