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A 2a and a 2b adenosine receptors affect HIF‐1α signaling in activated primary microglial cells
Author(s) -
Merighi Stefania,
Borea Pier Andrea,
Stefanelli Angela,
Bencivenni Serena,
Castillo Carlos Alberto,
Varani Katia,
Gessi Stefania
Publication year - 2015
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22861
Subject(s) - adenosine , biology , microglia , adenosine receptor , adenosine a2a receptor , microbiology and biotechnology , adenosine a3 receptor , angiogenesis , neuroinflammation , tumor necrosis factor alpha , receptor , inflammation , medicine , endocrinology , cancer research , immunology , biochemistry , agonist
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 A 2A through p44/42 and A 2B subtypes via p38 mitogen‐activated protein kinases (MAPKs) and Akt phosphorylation. Furthermore the nucleoside raised VEGF and decreased TNF‐α levels, by activating A 2B subtypes. In conclusion adenosine increases GLUT‐1 and iNOS gene expression in a HIF‐1α‐dependent way, through A 2A and A 2B receptors, 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 A 2B subtype. GLIA 2015;63:1933–1952