title: A2aand a2badenosine receptors affect HIF-1α signaling in activated primary microglial cells.
abstract: Microglia are central nervous system (CNS)-resident immune cells, that play a crucial role in neuroinflammation. Hypoxia-inducible factor-1 (HIF-1), the main transcription factor of hypoxia-inducible genes, is also involved in the immune response, being regulated in normoxia by inflammatory mediators. Adenosine is an ubiquitous nucleoside that has an influence on many immune properties of microglia through interaction with four receptor subtypes. The aim of this study was to investigate whether adenosine may affect microglia functions by acting on HIF-1α modulation. Primary murine microglia were activated with lipopolysaccharide (LPS) with or without adenosine, adenosine receptor agonists and antagonists and HIF-1α accumulation and downstream genes regulation were determined. Adenosine increased LPS-induced HIF-1α accumulation leading to an increase in HIF-1α target genes involved in cell metabolism [glucose transporter-1 (GLUT-1)] and pathogens killing [inducible nitric-oxide synthase (iNOS)] but did not induce HIF-1α dependent genes related to angiogenesis [vascular endothelial growth factor (VEGF)] and inflammation [tumor necrosis factor-α (TNF-α)]. The stimulatory effect of adenosine on HIF-1α and its target genes was essentially exerted by activation of A2Athrough p44/42 and A2Bsubtypes via p38 mitogen-activated protein kinases (MAPKs) and Akt phosphorylation. Furthermore the nucleoside raised VEGF and decreased TNF-α levels, by activating A2Bsubtypes. In conclusion adenosine increases GLUT-1 and iNOS gene expression in a HIF-1α-dependent way, through A2Aand A2Breceptors, suggesting their role in the regulation of microglial cells function following injury. However, inhibition of TNF-α adds an important anti-inflammatory effect only for the A2Bsubtype. GLIA 2015;63:1933-1952.
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato Di Mortara 17/19, Ferrara, 44121, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato Di Mortara 17/19, Ferrara, 44121, Italy.
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato Di Mortara 17/19, Ferrara, 44121, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Stefanelli
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato Di Mortara 17/19, Ferrara, 44121, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Bencivenni
authors.affiliation: Department of Nursing, Faculty of Nursing, Occupational and Speech Therapies, University of Castilla-La Mancha, Talavera De La Reina, Spain.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Castillo
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato Di Mortara 17/19, Ferrara, 44121, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.affiliation: Department of Medical Sciences, Pharmacology Section, University of Ferrara, via Fossato Di Mortara 17/19, Ferrara, 44121, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
keywords: GLUT-1; HIF-1α; TNF-α; VEGF; iNOS; inflammation; microglia cells; signaling pathways