Retinal microglial activation in glaucoma: evolution over time in a unilateral ocular hypertension model

Glaucoma is a neurodegenerative chronic pathology, characterized by the loss of retinal ganglion cells (RGC), which leads to an irreversible vision field loss. The increased intraocular pressure (IOP) constitutes its main risk factor. Nowadays, treatments for glaucoma are focused on decreasing IOP; nevertheless, progression disease continues, despite IOP control. This fact shows existence other factors that could contribute advance glaucomatous neurodegeneration. early diagnostics, use neuroprotective therapies, and knowledge pathological processes major challenges associated with management this disease. Different pathogenic mechanisms have been proposed be responsible RGC death, including oxidative stress, mitochondrial dysfunction, glutamate excitotoxicity, neuroinflammation (Casson et al., 2012). As in diseases, it has shown immune system may involved In retina optic nerve, as rest central nervous system, microglial constitute population resident cells, they play important role physiology survival (Neufeld, 1999; Yuan Neufeld, 2001). microglia able respond promptly damage, order maintain privilege. Initially, controlled response role, but state tissue damage maintained over time related activation resulting inflammatory process. Thus, protection mechanism against nerve damage. However, prolonged inflammation increase death RGC, thus contributing pathology 2001; Tezel 2009). glaucoma, demonstrated both humans experimental models (Vidal-Sanz phenotype alteration expression different receptors (CD200R, CX3CR1, P2Y12) release growth factors, pro-inflammatory cytokines (interleukin-1?, tumor necrosis factor-?, interleukin-6, etc.), cytotoxic substances (reactive oxygen nitric oxide species), well morphological changes (Ramírez 2015). Microglial (in rats or mice), hereditary induced, using techniques induction ocular hypertension (OHT) One studied detail laser-induced OHT mouse model, unilateral induced photocoagulation limbal episcleral veins animals, induces retrograde axonal transport RGCs subsequent degeneration these cells. 15 days after induction, exhibited signs activation, such proliferation migration areas retraction, reorientation, hyper-ramification their processes, appearance amoeboid- rod-like macrophagic capacity, (Gallego 2012; de Hoz 2013; Rojas 2014). macroglia (astrocytes Müller cells) also demonstrated, showing changes, overexpression glial fibrillary acidic protein addition, numerous rounded Iba-1+ CD68+ found close vessels. These monocytes enter alterations produced blood-retinal barrier (BRB) due neuroinflammatory process (Stolp Dziegielewska, 2009; infiltrated induce proinflammatory mediators activate stimulate macrophages, provoking neuronal gliosis immune-related surface markers, histocompatibility type II complex (MHC-II). molecule essential antigen presentation T physiological conditions, MHC-II restricted some at very low levels; however, context (tumor factor-? interferon-?) can lead (Tezel Ramírez was observed microglia, astrocytes, allowing T-cell-mediated presence co-stimulating required most were MHC-II+/ CD86–, only few amoebic having CD86+ immunolabeling. absence produce apoptosis anergy entered from bloodstream, causing downregulation adaptive response. immunomodulatory trigger playing neurotoxic adopting phenotypes, M1 (pro-inflammatory) M2 (neuroprotective). phenotypes continuous balance between two extreme states activation: state, secretion reactive species cytokines, anti-inflammatory secrete high levels neurotrophic (Parisi 2018). At marked anti Ym1, marker phenotype. indicates not exerting eyes 2013). Usually, bilateral affects eyes, do follow symmetric evolution. First, one eye appearing afterwards contralateral eye. Experimental whether show uninjured Morphological detected normotensive induction. addition astrocytes showed MHC-II. microgliosis upregulation support taking place 2013, Considering evidence involvement neuropathy cell exhaustive study how progresses would logical interesting step. A examined evolution points (1, 3, 5, 8, days) 2020). Two markers used identify microglia: Iba-1 P2RY12. allows analysis features purinergic P2RY12 receptor differentiation (P2RY12+) monocytes, infiltrating dendritic express marker. study, conducted soma size, arbor area, number vertical all layers present (the outer segment photoreceptor layer, plexiform (outer inner), fiber layer/ganglion layer (NFL-GCL)). Additionally, analyzed (Figure 1). 24 hours laser where located (de 2018; included shortening reorientation macrophage eye, although more intense time, there no area occupied NFL-GCL migratory phenomena size rather than IOP, remains model day 1 until drops normal values 7 days. RGCs, 2014; activated chemokines disruption BRB did MHC-II+ because P2RY12, bloodstream MHCII+ transformation ramified into amoeboid phagocytize had (more frequently eyes) change arrangement parallel perpendicular, sending towards neighboring plexuses connecting them. help transmission information layers, 2018).Figure 1: Major model.The “+” intensity changes. red color represents green IOP: Increased pressure; OHT: hypertension.Most 3 5 retraction (measured area) reaches maximum points. remained large days, smaller hours. sensitive resting down-regulation (Haynes 2006). native animals OHT, down-regulated begins slightly 8 reaching similar those naïve when occurs 1), coinciding highest From decreased slightly, increased, decreased, reach any h HTO persisted later time-points 2020) independent normotensive. Moreover, times point (soma number) less fairly stable analyzed. up-regulation (Rojas Conclusions: veins, produces even become normal. if them, originates confirms pathology. new approach treatment Knowledge moment intervene development therapies assist neuroprotection. work supported Ophthalmological Network OFTARED (RD16/0008/0005)‚ Institute Health Carlos III Spanish Ministry Economy (to AIR, RDH, JJS); Santander- Complutense University Madrid Research Projects (PR75/18-21560) RNH, José A. Fernández-Albarral currently Predoctoral Fellowship (FPU17/01023) Science, Innovation, Universities.