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.
Highlights
Glaucoma is a main cause of visual impairment and a leading cause of irreversible blindness worldwide [1]
Neuroinflammation has a cardinal role in glaucoma and microglial cells have been described as major pInlam[oy5r,aed9jr,oe1sNrr0f]tpoe.ourlIanmrtyohoeiiemnrrsdifinlefcaofrmleratlommethvmameatitiimaoentdnfiolcahrIeOymalsePemv,anaatvchttaieoerrdrodcynIeiOnelmlnaPselv,wnritrohteo,lerencecomiencnlhelgtnsarlitlawbl,ueucencortogeinnmetcgrdhaibatwaoulnlietgtdinhnlagmgeuelitdcecoovrwogmagilttaealhiudtaocelhuolceymsevdlnaalrstteoeohusduartsaovhtdeynicdeebgurpeoeerrosnnetdseadsertueaigcsrteciepnorr(einbeErseaH[s5dtuiP,o9ar)n,es1f0o]r. 4 o(rE2H4Ph),foars 4woerp2r4ehv,ioaus swlye dpreemvioonusstlryatdeedmtohnasttEraHtePdttrhigatgEerHsPmtircigroggelrisamreicarcotigvliiatyre[2a6ct]i.vity [26]
This work demonstrates that the activation of A3 receptor (A3R) is able to control microglia reactivity elicited by elevated pressure. This is an in vitro study in which the contribution of other cells is not considered, but future studies evaluating whether A3R agonists can control microglia-mediated neuroinflammation in an animal model of ocular hypertension will help clarifying the potential anti-inflammatory effects of A3R activation. Taken these results showing that 2-Cl-IB-MECA reduces pro-inflammatory microglia responses elicited by elevated pressure and our previous reports [23,24], one may envisage that A3R activation may have protective properties to retinal ganglion cell (RGC) in glaucomatous conditions, by triggering survival mechanisms directly on A3R-expressing RGCs, and by controlling microglia reactivity
Summary
Glaucoma is a main cause of visual impairment and a leading cause of irreversible blindness worldwide [1]. It is described as a group of optic neuropathies that presents common characteristics such as retinal ganglion cell (RGC) loss, thinning of the retinal nerve fiber layer and cupping of the optic disc [2]. Elevated intraocular pressure (IOP) is the main risk factor for disease onset and progression. Microglia become reactive early in the course of the disease and have been. Htheerpeiont,enwtieasl hoof wA3Rthat 2-Cagl-oIBn-isMt iEnCcAon, ttrhoellsineglemctiivcreoAgl3iaRraegacotnivisitty, ctoringtgreorlesdmbiycreolgevliaateredapcrtievsistuyr, es.uHgegreesitnin, wg ethsahto, wintahdatd2it-iColn- to cgolancIuBofec-nMorfemnEreCanuAebruyo, rptcohropeonrtosteretcoelteclilctoiitnonivgnbembyAyidc3dRirroieragecglctiotlaylny-mitstataer,rdggceioeattntiinentrdggolnRRseGGmuCCriocssr,i,noAAflg33laRiRamaarmgegoaaonctntiisoiivtsnsitt.smym,asyauygcogcnoefsnetfirneprgrpotrhtoeacttet,icoitnnioatnoddtRoiGtRioCGnsCtinos in glaucoma by controlling microglia-mediated neuroinflammation
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