Activation of Adenosine A3 Receptor Inhibits Microglia Reactivity Elicited by Elevated Pressure

Abstract

Glaucoma is a progressive chronic retinal degenerative disease and a leading cause of global irreversible blindness, characterized by optic nerve damage and retinal ganglion cell (RGC) death. Elevated intraocular pressure (IOP) is a main risk factor of glaucoma. Neuroinflammation plays an important role in glaucoma. We have been demonstrating that elevated pressure triggers microglia reactivity that contribute to the loss of RGCs. Adenosine, acting on adenosine receptors, is a crucial modulator of microglia phenotype. Microglia express all adenosine receptors. Previously, we demonstrated that the activation of adenosine A3 receptor (A3R) affords protection to the retina, including RGCs, unveiling the possibility for a new strategy for glaucoma treatment. Since microglial cells express A3R, we now studied the ability of a selective A3R agonist (2-Cl-IB-MECA) in controlling microglia reactivity induced by elevated hydrostatic pressure (EHP), used to mimic elevated IOP. The activation of A3R reduced EHP-induced inducible nitric oxide synthase (iNOS) expression, microglia migration and phagocytosis in BV-2 cells. In retinal microglia, proliferation and phagocytosis elicited by EHP were also decreased by A3R activation. This work demonstrates that 2-Cl-IB-MECA, the selective agonist of A3R, is able to hinder microglia reactivity, suggesting that A3R agonists could afford protection against glaucomatous degeneration through the control of neuroinflammation.

Adenosinergic Signaling as a Key Modulator of the Glioma Microenvironment and Reactive Astrocytes

“…In the CNS, the P2X7 receptor is preferentially located on microglia ( Illes, 2020 ). Besides that, several authors have also been reported the expression of P1 receptors in microglia, describing ADO as a crucial modulator of microglia phenotype of CNS pathologies, including cancer ( Hammarberg et al, 2003 ; Synowitz et al, 2006 ; Ferreira-Silva et al, 2020 ).…”

Adenosine and Inflammation: Here, There and Everywhere

“…A reduction of microglia activation was also observed stimulating A 3 ARs with the agonist IB-MECA, an effect likely underlining their antinociceptive action [ 172 ]. The selective A 3 AR agonist 2-Cl-IB-MECA was effective in controlling microglia reactivity induced by elevated hydrostatic pressure, with potential positive repercussions in glaucoma [ 173 ]. In a model of subarachnoid hemorrhage, 2-CI-IB-MECA markedly directed microglia towards the M2, or more precisely M(IL-4) phenotype, reduced inflammation, and improved neurological dysfunction [ 174 ].…”

New strategies for neuro protection in glaucoma

“…Blocking microglial A2A R prevents microglial cell response to elevated pressure and it is sufficient to protect retinal cells from elevated pressure-induced death ( Aires et al, 2019 ). Another study found activation of Adenosine A (3) receptor could hinder the microglia reactivity ( Ferreira-Silva et al, 2020 ), attenuated the impairment in retrograde axonal transport, and afford protection against glaucomatous degeneration. In addition, P2X7 receptor antagonist protects retinal ganglion cells by inhibiting microglial activation in a rat chronic ocular hypertension model ( Dong et al, 2018 ).…”