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P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis
Alazne Zabala1, Nuria Vazquez-Villoldo1, Björn Rissiek2
1Achucarro Basque Center for Neurosciences, CIBERNED and Departamento de Neurociencias, Universidad del País Vasco, Leioa, Spain.
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.
Insights
Purinergic receptor P2X4 (P2X4R) plays a crucial role in regulating microglia responses during autoimmune inflammation. Modulating P2X4R with ivermectin promotes myelin repair and reduces disease severity in models of neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia are key immune cells in the central nervous system, essential for inflammation and repair.
- Understanding microglia's role in pathology is vital for developing regenerative strategies.
- Purinergic receptor P2X4 (P2X4R) is implicated in immune cell function.
Purpose of the Study:
- To investigate the role of P2X4R in microglia/macrophages during autoimmune inflammation.
- To evaluate the therapeutic potential of P2X4R modulation in demyelinating diseases.
Main Methods:
- Experimental autoimmune encephalomyelitis (EAE) model for autoimmune inflammation.
- Lysolecithin-induced demyelination model for myelin repair assessment.
- In vitro studies on oligodendrocyte differentiation.
Main Results:
- P2X4R blockade worsened EAE, promoted pro-inflammatory microglia, and inhibited myelin phagocytosis.
- P2X4R blockade halted oligodendrocyte differentiation and remyelination.
- Ivermectin (IVM) treatment shifted microglia to an anti-inflammatory phenotype, enhanced myelin phagocytosis, and promoted remyelination, ameliorating EAE.
- IVM treatment promoted remyelination in the lysolecithin model.
Conclusions:
- P2X4R signaling critically modulates microglia/macrophage responses in neuroinflammation.
- Ivermectin (IVM) emerges as a potential therapeutic agent for promoting myelin repair and treating demyelinating conditions.
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