Induction of GPR17 receptor expression in microglial cells

Microglial cells are resident macrophages in the central nervous system and, after insults, act by migrating to the site of injury, phagocyting cell debris and secreting inflammatory mediators. Known players in the inflammation process are cytokines, chemokines, arachidonic acid metabolites (cysteinyl leukotrienes, cysLTs) and purinergic molecules. The recently discovered GPR17 is structurally related to known P2Y receptors and CysLT receptors and responds to both uracil nucleotides (like UDP, UDP-glucose) and cysLTs (like LTD4). Little is known about the regulation of GPR17 in microglia except that, in animal models, GPR17 has been found in these cells exclusively after ischemic or traumatic injury. The aim of this study was to identify in vitro the signals that can trigger GPR17 expression in reactive microglia in vivo. To this purpose, primary microglial cultures from rat brain were exposed to various activating agents and GPR17 expression measured by real time PCR. Results indicate that GPR17 receptors are present in rat microglia cells at very low level. Conditioned medium from oxygen and glucose deprivated neurons increased their expression; however, typical “danger signals” (ATP, LTD4) were not responsible for this process. Curiously, lipopolysaccharide did not cause an increase but indeed decreased GPR17 expression. UDP, UDP-glucose and Zymosan, a yeast cell wall glucan, led to increase of GPR17 expression in a time-dependent manner and the latter also caused also dramatic changes of microglia morphology. It remains to be determined how long GPR17 receptors remains in the membrane and whether their stimulation favors a detrimental or a beneficial activated microglia phenotype.