The role of phagocytosis for modulation and clearance of pathological angiogenesis.

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Proliferative retinopathies, such as retinopathy of prematurity (ROP) or proliferative diabetic retinopathy (DR) represent an important health burden being a major cause of blindness. Proliferative retinopathies are characterized by pathological neovascularization (angiogenesis) in the retina leading to the formation of aberrant neo-vessels, so called tufts, which protrude beyond the retinal inner limiting membrane into the vitreous cavity, causing severe vision impairment. Interestingly we observed, that endothelial cell apoptosis is a hallmark of these tufts, which might initiate the process of tuft regression and vessel normalization, observed in ROP. A major component of the pathophysiology underlying retinopathy is the close interplay of endothelial cells with inflammatory cells that is regulated by specific components of the micro-environment, e.g. local hypoxia/ reoxygenation. The aim of the present proposal is to investigate whether the phagocytic property of microglia is involved in the clearance of apoptotic endothelial cells in the pathological tufts during ROP and thus modulates pathological angiogenesis in the context of proliferative retinopathy. We will address this question by engaging microglia-specific deletion of SOCS3 as a specific tool, as we have preliminary evidence, that this factor regulates phagocytosis. In particular, we will assess (I) whether microglial Socs3, with its altered phagocytic capacity, can affect in-vivo physiological and pathological retinal angiogenesis by engaging the mouse hypoxia-induced vasoproliferative retinopathy of prematurity (ROP) model. (II) In addition, we want to identify with the help of reporter mice, whether in vivo endothelial cells or endothelial cell particles are taken up by microglia and we will study the expression kinetics of pro- and anti-phagocytic molecules in the mouse ROP-model. (III) Moreover we will analyse whether hypoxia/reoxigenation and/ or the uptake of apoptotic endothelial cells are stimuli to reprogram myeloid cells towards a pro-efferocytic and pro-resolving phenotype. (IV) Finally, as a proof of principle, we will evaluate if the modulation of apoptotic cell clearance (efferocytosis) by mononuclear cells can be used as a new therapeutic strategy for the treatment of pathological vascular disorders. Despite the progress made in the last years, understanding the pathogenesis of retinopathy, the knowledge of the underlying mechanisms and the interaction of endothelial and inflammatory cells is still insufficient and therapeutics are limited. Therefore, this proposal is highly innovative, since it will provide novel mechanistic insights into the role of microglia cell phagocytic activity in the context of proliferative retinopathy. The improved understanding of the underlying mechanism may subsequently lead to novel therapeutic concepts to prevent blindness.