Inhibition of inflammatory cells delays retinal degeneration in experimental retinal vein occlusion in mice

Abstract

The role of microglia in retinal inflammation is still ambiguous. Branch retinal vein occlusion initiates an inflammatory response whereby resident microglia cells are activated. They trigger infiltration of neutrophils that exacerbate blood–retina barrier damage, regulate postischemic inflammation and irreversible loss of neuroretina. Suppression of microglia‐mediated inflammation might bear potential for mitigating functional impairment after retinal vein occlusion (RVO). To test this hypothesis, we depleted microglia by PLX5622 (a selective tyrosine kinase inhibitor that targets the colony‐stimulating factor‐1 receptor) in fractalkine receptor reporter mice (Cx3cr1gfp/+) subjected to various regimens of PLX5622 treatment and experimental RVO. Effectiveness of microglia suppression and retinal outcomes including retinal thickness as well as ganglion cell survival were compared to a control group of mice with experimental vein occlusion only. PLX5622 caused dramatic suppression of microglia. Despite vein occlusion, reappearance of green fluorescent protein positive cells was strongly impeded with continuous PLX5622 treatment and significantly delayed after its cessation. In depleted mice, retinal proinflammatory cytokine signaling was diminished and retinal ganglion cell survival improved by almost 50% compared to nondepleted animals 3 weeks after vein occlusion. Optical coherence tomography suggested delayed retinal degeneration in depleted mice. In summary, findings indicate that suppression of cells bearing the colony‐stimulating factor‐1 receptor, mainly microglia and monocytes, mitigates ischemic damage and salvages retinal ganglion cells. Blood–retina barrier breakdown seems central in the disease mechanism, and complex interactions between different cell types composing the blood–retina barrier as well as sustained hypoxia might explain why the protective effect was only partial.

Therapeutic Targeting of Retinal Immune Microenvironment With CSF-1 Receptor Antibody Promotes Visual Function Recovery After Ischemic Optic Neuropathy

“…These reports are in agreement with our qPCR results in the present study. The suppression of the pro-inflammatory cytokines by administration of CSF-1R antagonist has also been documented (49). Importantly, weekly administration of CSF-1RAb in our study is sufficient to maintain the suppression of microglial, macrophage, and T cell activations beyond 14 days post injury.…”

Retinal ganglion cell survival after severe optic nerve injury is modulated by crosstalk between JAK/STAT signaling and innate immune responses in the zebrafish retina

“…These data suggest that macrophage/microglia-mediated inflammation might contribute to RGC death after ONT, in opposition to JAK/STAT-mediated neuroprotection. To test this hypothesis, we inhibited inflammation after ONT via dexamethasone treatment, a strategy shown to protect RGCs in other injury models (Bollaerts et al, 2019; Dutt et al, 2010; Gallina et al, 2015; Jovanovic et al, 2020), and quantified RGC survival. Experimentally, 2μL of 100μM dexamethasone or 0.05% DMSO (vehicle control) was IV injected into isl2b :GFP fish at the time of ONT and again at 1dpi and tissue was collected at 7dpi (after Fig.…”

“…Previous reports have identified roles for microglia in contributing to RGC death after a variety of insults (Bosco et al, 2008; Jovanovic et al, 2020; Takeda et al, 2018). However, other studies have shown that microglia are dispensable for RGC survival after ON crush (Hilla et al, 2017), and may instead provide neuroprotective and/or pro-regenerative signals (Bell et al, 2018; Sappington et al, 2006).…”

“…Previous reports have identified roles for microglia in contributing to RGC death after a variety of insults (Bosco et al, 2008;Jovanovic et al, 2020;Takeda et al, 2018).…”

Mesenchymal Stem Cell-Based Therapy for Retinal Degenerative Diseases: Experimental Models and Clinical Trials

“…Furthermore, different populations of glial cells expressing genes associated with AMD (such as VEGFA and HTRA1 ), have been identified in the retina with this type of disease [ 7 ]. Alternatively, it has been shown that the inhibition of the microglia delays retinal degeneration in the experimental retinal vein occlusion in mice [ 8 ].…”