The A1 adenosine receptor as a new player in microglia physiology

Abstract

The purinergic system is highly involved in the regulation of microglial physiological processes. In addition to the accepted roles for the P2 X4,7 and P2 Y12 receptors activated by adenosine triphosphate (ATP) and adenosine diphosphate, respectively, recent evidence suggests a role for the adenosine A2A receptor in microglial cytoskeletal rearrangements. However, the expression and function of adenosine A1 receptor (A1AR) in microglia is still unclear. Several reports have demonstrated possible expression of A1AR in microglia, but a new study has refuted such evidence. In this study, we investigated the presence and function of A1AR in microglia using biomolecular techniques, live microscopy, live calcium imaging, and in vivo electrophysiological approaches. The aim of this study was to clarify the expression of A1AR in microglia and to highlight its possible roles. We found that microglia express A1AR and that it is highly upregulated upon ATP treatment. Moreover, we observed that selective stimulation of A1AR inhibits the morphological activation of microglia, possibly by suppressing the Ca(2+) influx induced by ATP treatment. Finally, we recorded the spontaneous and evoked activity of spinal nociceptive-specific neuron before and after application of resting or ATP-treated microglia, with or without preincubation with a selective A1AR agonist. We found that the microglial cells, pretreated with the A1AR agonist, exhibit lower capability to facilitate the nociceptive neurons, as compared with the cells treated with ATP alone.

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

“…Furthermore, NGF has been shown to induce microglial migration, and this cell migration is modulated by TGF-b, which also has a chemotactic activity (Ambrosini and Aloisi, 2004;De Simone et al, 2007;Paglinawan et al, 2003). Migration can also be stimulated by nucleotides, such as extracellular ATP and ADP, which are released in response to ischemic and traumatic CNS injuries and interact with several purinoceptors (Honda et al, 2001;Inoue et al, 2007;Luongo et al, 2014). Moreover, the microglial response depends on initial cytokine stimulation .…”

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…Further, A 2A R activation on microglia induces COX-2 expression (Fiebich et al, 1996), an important marker and mediator of inflammation. The effect of microglial A 1 receptor activation can be either pro-or anti-inflammatory, depending on other factors in the environment (Hasko et al, 2005); however, both neuroinflammation and microglial activity is enhanced in an A 1A knockout mouse strain under pathological conditions, suggesting that the primary role of A 1A receptor signaling is anti-inflammatory (Luongo et al, 2014).…”

CNS macrophages and peripheral myeloid cells in brain tumours

“…Extracellular adenosine itself is not only a passive product of tumour induced ischemia, hypoxia and necrosis but also actively released due to altered purine metabolism [85]. [88,145].…”