P2x7 receptors control demyelination and inflammation in the cuprizone model

• Published in: Brain, behavior, & immunity. Health behavior, & immunity. Health, 2020-04, Vol.4, p.100062-100062, Article 100062
• Main Authors: Bernal-Chico, Ana, Manterola, Andrea, Cipriani, Raffaela, Katona, István, Matute, Carlos, Mato, Susana
• Format: Article
• Language: English
• Subjects: Cuprizone; De- and remyelination; Full Length; Inflammation; Microglia; Multiple sclerosis; P2x7 receptors
• ISSN: 2666-3546; 2666-3546
• DOI: 10.1016/j.bbih.2020.100062

The contribution of P2x7 receptors to multiple sclerosis remains controversial, as both detrimental and beneficial effects resulting from P2x7 receptor loss-of-function have been reported in autoimmune models of the disease. Here we investigated the relevance of P2x7 receptors to de- and remyelination in the cuprizone model of T cell-independent myelin degeneration. Primary demyelination was induced by administration of 0.3% cuprizone in the diet for 3 and 6 weeks. Remyelination was studied in mice treated with the P2x7 receptor antagonists Brilliant Blue G (BBG, 50 ​mg/Kg) and JNJ-47965567 (30 ​mg/Kg) for 2 weeks following 6 weeks of cuprizone challenge. Toxic demyelination induced a robust up-regulation of P2x7 receptors mainly localized on microglial cells. In parallel, we measured increased expression of several NLPR3-inflammasome and M1 polarization-associated genes in demyelinated tissue. Notably, mice deficient in P2x7 receptors exhibited attenuated demyelination, reduced presence of M1 microglia and reactive astrocytes as well as blunted expression of pro-inflammatory genes in response to cuprizone feeding. Nevertheless, blockade of P2x7 receptors during the remyelination phase did not improve the extent of myelin recovery nor attenuated glial reaction and inflammation in damaged white matter. These findings suggest that P2x7 receptors drive T cell-independent inflammation and demyelination, but are not relevant to regenerative responses involved in myelin repair. •The role of P2x7 receptors in multiple sclerosis remains controversial.•P2x7 receptors during myelin damage and repair in the cuprizone model.•Cuprizone up-regulated P2x7 receptors, NLPR3-inflammasome and M1 polarization genes.•Attenuated demyelination and inflammation by cuprizone in P2x7 knockouts.•Antagonists did not promote remyelination; P2x7 not relevant to myelin regeneration.