Abstract
Inflammation is increasingly recognized as an important modulator in the pathogenesis of neovascular age-related macular degeneration (nAMD). Although significant progress has been made in delineating the pathways that contribute to the recruitment of inflammatory cells and their contribution to nAMD, we know little about what drives the resolution of these inflammatory responses. Gaining a better understanding of how immune cells are cleared in the choroid will give a novel insight into how sustained inflammation could influence the pathogenesis of nAMD. The pro-apoptotic Bcl-2 family member Bim is a master regulator of immune cell homeostasis. In its absence, immune cell lifespan and numbers increase. Most therapeutic regimes that squelch inflammation do so by enhancing immune cell apoptosis through enhanced Bim expression and activity. To test the hypothesis that Bim expression tempers inflammation during the pathogenesis of nAMD, we used the mouse laser-induced choroidal neovascularization (CNV) model in which inflammation acts as a facilitator of CNV. Here, we showed minimal to no change in the recruitment of F4/80-, CD80-, CD11b-, and Iba1-positive myeloid-derived mononuclear phagocytes to the site of laser photocoagulation in the absence of Bim expression. However, the resolution of these cells from the choroid of Bim-deficient (Bim -/-) mice was significantly diminished following laser photocoagulation. With time, we noted increased scar formation, demonstrated by collagen I staining, in Bim -/- mice with no change in the resolution of neovascularization compared to wild-type littermates. We also noted that mice lacking Bim expression in mononuclear phagocytes (BimFlox/Flox; Lyz2-Cre (BimMP) mice) had delayed resolution of F4/80-, CD80-, CD11b-, and Iba1-positive cells, while those lacking Bim expression in endothelial cells (BimFlox/Flox; Cad5-Cre (BimEC) mice) had delayed resolution of only CD11b- and Iba1-positive cells. Both BimMP and BimEC mice demonstrated increased scar formation, albeit to differing degrees. Thus, our studies show that resolving inflammation plays an important role in moderating scar formation in nAMD, and it is impacted by Bim expression in both the endothelium and mononuclear phagocyte lineages.
Highlights
Inflammation plays a central role in the pathogenesis of neovascular eye diseases including exudative/neovascular age-related macular degeneration, retinopathy of prematurity (ROP), and diabetic retinopathy
Vascular endothelial growth factor (VEGF) expression is essential for the maintenance of the retinal pigment epithelium (RPE) and the health of the choriocapillaris, its increased expression contributes to choroidal neovascularization (CNV) and leakiness of the choroidal vessels
We showed that a lack of Bim expression in myeloid-derived Mononuclear phagocytes (MPs) was sufficient to diminish the resolution of F4/80, CD80, Iba1, and CD11b-positive cells and increase scar formation
Summary
Inflammation plays a central role in the pathogenesis of neovascular eye diseases including exudative/neovascular age-related macular degeneration (nAMD), retinopathy of prematurity (ROP), and diabetic retinopathy. The visual deficit that initially arises from retinal degeneration (dry AMD) is often complicated by the secondary effects of choroidal neovascularization (CNV) (wet or nAMD) [1]. Maintenance of the choroidal circulation facilitates photoreceptor and outer retinal health, and its disruption contributes to the pathogenesis of sight-threatening eye diseases such as AMD. CNV-related neovascularization, originating in the choroid, extends through the Bruch’s membrane to the RPE layer, with the loss of the RPE and photoreceptor cells compromising vision [3]. Vascular endothelial growth factor (VEGF) expression is essential for the maintenance of the RPE and the health of the choriocapillaris, its increased expression contributes to CNV and leakiness of the choroidal vessels
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