Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco, Leioa, Spain.
Department of Neurology, University Medical Center, Hamburg, Germany.
EMBO Mol Med. 2018 Aug;10(8). doi: 10.15252/emmm.201708743.
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 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.
小胶质细胞检测大脑微环境中的损伤或感染信号，对于启动和解决病原体或组织损伤引起的炎症至关重要。因此，了解小胶质细胞在病理过程中的反应机制对于促进再生反应至关重要。在这里，我们分析了嘌呤能受体 P2X4（P2X4R）在自身免疫性炎症中小胶质细胞/巨噬细胞中的作用。P2X4R 信号阻断在实验性自身免疫性脑脊髓炎（EAE）模型中加重了临床症状，也有利于小胶质细胞向促炎表型激活，并抑制髓磷脂吞噬。此外，小胶质细胞中 P2X4R 的阻断在溶血磷脂酰胆碱诱导脱髓鞘后阻止少突胶质细胞分化和髓鞘再生。相反，别构调节剂伊维菌素（IVM）增强 P2X4R 信号转导有利于小胶质细胞向抗炎表型转变，增强髓磷脂吞噬，促进髓鞘再生反应，并改善 EAE 的临床症状。我们的研究结果为 P2X4Rs 调节小胶质细胞/巨噬细胞炎症反应提供了证据，并确定 IVM 是目前用于促进髓磷脂损伤修复的药物中的潜在候选药物。
