P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis
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P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis. / Zabala, Alazne; Vazquez-Villoldo, Nuria; Rissiek, Björn; Gejo, Jon; Martin, Abraham; Palomino, Aitor; Perez-Samartín, Alberto; Pulagam, Krishna R; Lukowiak, Marco; Capetillo-Zarate, Estibaliz; Llop, Jordi; Magnus, Tim; Koch-Nolte, Friedrich; Rassendren, Francois; Matute, Carlos; Domercq, María.
in: EMBO MOL MED, Jahrgang 10, Nr. 8, 08.2018, S. UNSP e8743.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis
AU - Zabala, Alazne
AU - Vazquez-Villoldo, Nuria
AU - Rissiek, Björn
AU - Gejo, Jon
AU - Martin, Abraham
AU - Palomino, Aitor
AU - Perez-Samartín, Alberto
AU - Pulagam, Krishna R
AU - Lukowiak, Marco
AU - Capetillo-Zarate, Estibaliz
AU - Llop, Jordi
AU - Magnus, Tim
AU - Koch-Nolte, Friedrich
AU - Rassendren, Francois
AU - Matute, Carlos
AU - Domercq, María
N1 - © 2018 The Authors. Published under the terms of the CC BY 4.0 license.
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.15252/emmm.201708743
DO - 10.15252/emmm.201708743
M3 - SCORING: Journal article
C2 - 29973381
VL - 10
SP - UNSP e8743
JO - EMBO MOL MED
JF - EMBO MOL MED
SN - 1757-4676
IS - 8
ER -
