Zabala-Olaizola, A. 1 , Palomino, A. 1 , Vazquez-Villoldo, N. . 1 , Matute, C. 1 & Domercq, M. 1
1 Departamento de Neurociencias, Universidad del País Vasco-UPV/EHU, 48940 Leioa, Spain,
2 Achucarro Basque Center for Neuroscience-UPV/EHU, 48170 Zamudio, Spain
3 Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red
P2X4 receptors modulates microglial polarization
Alazne Zabala-Olaizola, Aitor Palomino, Nuria Vazquez-Villoldo, Carlos Matute* and María Domercq*
* Corresponding authors; carlos.matute@ehu.es or maria.domercq@ehu.es
Microglial activation is an integral part of neuroinflammation contributing to neurological damage in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). We have previously shown that P2X4 receptor is overexpressed in activated microglia in the spinal cord of EAE rats and in human MS optic nerve samples. Because microglial polarization to an M2 phenotype favors remyelination in the EAE model (Miron et al., 2014), we have analyzed the role played by P2X4 receptor in microglial polarization. The blockage of P2X4 receptors in cultured microglia favors M1 differentiation and significantly inhibits M2 polarization. Factors controlling microglial polarization, like macrophage granulocyte colony stimulating factor (MG-CSF; M1-inducing factor) and macrophage colony stimulating factor (M-CSF; M2-inducing factor), also induces multinucleated giant cell formation. Surprisingly, P2X4 receptor blockage exclusively antagonized M-CSF induced multinucleation, suggesting a possible interaction with CSF-1R signaling pathway. Moreover, preliminary data showed that conditioned medium from M1 and M2 microglia differentially controls oligodendrocyte development and that P2X4 receptor blockage significantly reduces M2-dependent oligodendrocyte differentiation. Accordingly, blocking P2X4R inhibits remyelination whereas potentiating P2X4R signaling favors remyelination in cerebellar organotypic cultures after lysolecithin treatment. These results suggest that microglial P2X4 receptor could be a target to promote remyelination in demyelinating diseases.