The role of phagocytosis for modulation and clearance of pathological angiogenesis.
Anatomy and Physiology
Final Report Abstract
Proliferative retinal diseases, including diabetic retinopathy and retinopathy of prematurity (ROP), are the most common sight-threatening diseases in the Western world. Inflammation and hypoxia (lack of oxygen supply to tissue) of the retina play an important role in the pathogenesis of these retinopathy diseases. This is caused by a dysfunction of the endothelial cells that form the microvessels of the retina. As a result of this dysfunction, new blood vessels (angiogenesis) form, which disrupts the path of light to the photoreceptors and can therefore lead to impaired vision and even blindness. The therapies currently available (laser treatment and injection of VEGF inhibitors) are inadequate for the patient because they have side effects and often cannot permanently halt the progression of the disease or improve vision. The aim is to develop new and better treatment methods for patients with proliferative retinopathy that prevent the formation of new pathological blood vessels. Although it is generally recognized that inflammatory cells contribute to both physiological and pathological angiogenesis of the retina, our knowledge of various processes and underlying mechanisms, especially with regard to the direct interaction with endothelial cells, is still very limited. Therefore, the investigation of these mechanisms is crucial to develop new potential intervention therapies. In this project, we specifically looked at the role of phagocytosis of apoptotic endothelial cells by resident immune cells (microglia) in the context of pathological angiogenesis in the mouse model of oxygen-induced retinopathy (OIR). We used endotheliumspecific fluorescent reporter mice to investigate the kinetics of endothelial cell uptake by microglia in the OIR model. Our data showed that there was an increased number of phagocytic microglia in the immediate vicinity of the pathological vessels and that we observed an altered phagocytosis rate in different stages of the OIR model compared to controls. In addition, we were able to show that genetically modified mice with increased Growth Arrest Specific 6 (GAS6)-mediated phagocytic activity developed reduced pathological neovascularization in the OIR model, which could be reversed by GAS6 neutralization. Furthermore, we were able to show in cell culture experiments that exogenous GAS6 supplementation increased microglial phagocytosis, which also limited pathological neovascularization in therapy studies in the mouse OIR model. In summary, it can be said that promoting the phagocytosis of immune cells by modulating GAS6 represents a potential new target for the treatment of pathological neovascularization in proliferative retinal diseases.
Link to the final report
https://doi.org/10.4126/FRL01-006525039
Publications
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Myeloid SOCS3 Deficiency Regulates Angiogenesis via Enhanced Apoptotic Endothelial Cell Engulfment. Journal of Innate Immunity, 12(3), 248-256.
Korovina, Irina; Neuwirth, Ales; Sprott, David; Troullinaki, Maria; Poitz, David M.; Deussen, Andreas & Klotzsche-von, Ameln Anne
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Harnessing retinal phagocytes to combat pathological neovascularization in ischemic retinopathies?. Pflügers Archiv - European Journal of Physiology, 474(6), 575-590.
Klotzsche-von, Ameln Anne & Sprott, David
