title: P2X4 receptors control the fate and survival of activated microglia.
abstract: Microglia, the resident immune cells of the central nervous system, responds to brain disarrangements by becoming activated to contend with brain damage. Here we show that the expression of P2X4 receptors is upregulated in inflammatory foci and in activated microglia in the spinal cord of rats with experimental autoimmune encephalomyelitis (EAE) as well as in the optic nerve of multiple sclerosis patients. To study the role of P2X4 receptors in microgliosis, we activated microglia with LPS in vitro and in vivo. We observed that P2X4 receptor activity in vitro was increased in LPS-activated microglia as assessed by patch-clamp recordings. In addition, P2X4 receptor blockade significantly reduced microglial membrane ruffling, TNFα secretion and morphological changes, as well as LPS-induced microglial cell death. Accordingly, neuroinflammation provoked by LPS injection in vivo induced a rapid microglial loss in the spinal cord that was totally prevented or potentiated by P2X4 receptor blockade or facilitation, respectively. Within the brain, microglia in the hippocampal dentate gyrus showed particular vulnerability to LPS-induced neuroinflammation. Thus, microglia processes in this region retracted as early as 2 h after injection of LPS and died around 24 h later, two features which were prevented by blocking P2X4 receptors. Together, these data suggest that P2X4 receptors contribute to controlling the fate of activated microglia and its survival.
authors.affiliation: Departamento de Neurociencias, Universidad del País Vasco-UPV/EHU, Barrio Sarriena s/n, 48940, Leioa, Spain, Achucarro Basque Center for Neuroscience-UPV/EHU, 48170, Zamudio, Spain, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 48940, Leioa, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Vázquez-Villoldo
authors.forename: María
authors.initials: M
authors.lastname: Domercq
authors.forename: Abraham
authors.initials: A
authors.lastname: Martín
authors.forename: Jordi
authors.initials: J
authors.lastname: Llop
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gómez-Vallejo
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019070:Cell Lineage; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058848:Receptors, Purinergic P2X4 / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D058848:Receptors, Purinergic P2X4; D000255:Adenosine Triphosphate
keywords: EAE and multiple sclerosis; P2X4 purinergic receptor; cell death; microglia