Yilmaz Canelif, Korovina Irina, Witt Anke, Abdallah Farid, Müller Bianca, Hentsche Carmen, Fleischhauer Anika, Speier Stephan, Deussen Andreas, Klotzsche-von Ameln Anne
Institute of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.
Cell Death Dis. 2025 Jun 2;16(1):428. doi: 10.1038/s41419-025-07744-4.
Ischemic retinopathies (IR) are major causes of blindness worldwide. They are characterized by an exuberant hypoxia-driven pathological neovascularization (NV). While it is well accepted that immune cells contribute to both physiological and pathological retinal angiogenesis, our knowledge of various processes and underlying mechanisms, especially in the direct interaction with endothelial cells (EC), is still very limited. Here, we addressed the role of microglial phagocytosis of apoptotic EC in the context of pathological hypoxia-related NV in the mouse oxygen-induced retinopathy model (OIR). We utilized endothelium-specific fluorescent reporter mice to study the kinetics of EC phagocytosis by leukocytes in OIR. Indeed, we observed phagocytic microglia in close proximity to the pathological vessels and an altered phagocytosis rate by flow cytometry compared to controls. We observed a decrease in the phagocytic rate in early hypoxia-driven stages of OIR, whereas in later stages where pathological vessels appear, the phagocytosis rate was increased. Myeloid-specific deletion of the suppressor of cytokine signaling protein 3 (SOCS3) was previously shown to induce increased phagocytic activity due to overexpression of the opsonin molecule growth arrest-specific 6 (GAS6). In myeloid SOCS3-deficient mice, we observed a reduction of pathological NV in OIR. This reduction could be reversed by neutralizing GAS6 via administration of recombinant MERTK protein, the receptor for GAS6 expressed on myeloid cells. Furthermore, exogenous GAS6 supplementation increased microglial phagocytosis in vitro and limited pathological NV in OIR. Our data suggest that the promotion of immune cell phagocytosis by the modulation of the GAS6-MERTK axis might represent a potential target for the treatment of pathological NV in IR.
缺血性视网膜病变（IR）是全球失明的主要原因。其特征是由严重缺氧驱动的病理性新生血管形成（NV）。虽然免疫细胞在生理性和病理性视网膜血管生成中均起作用这一点已得到广泛认可，但我们对各种过程及其潜在机制的了解，尤其是与内皮细胞（EC）直接相互作用方面的了解，仍然非常有限。在此，我们在小鼠氧诱导性视网膜病变模型（OIR）中，探讨了凋亡EC的小胶质细胞吞噬作用在病理性缺氧相关NV背景下的作用。我们利用内皮细胞特异性荧光报告小鼠来研究OIR中白细胞对EC的吞噬动力学。事实上，我们观察到病理性血管附近存在吞噬性小胶质细胞，并且与对照组相比，通过流式细胞术检测到吞噬率发生了改变。我们观察到在OIR早期缺氧驱动阶段吞噬率降低，而在出现病理性血管的后期阶段，吞噬率增加。先前的研究表明，髓系特异性缺失细胞因子信号传导抑制蛋白3（SOCS3）会因调理素分子生长停滞特异性6（GAS6）的过表达而诱导吞噬活性增加。在髓系SOCS3缺陷小鼠中，我们观察到OIR中病理性NV减少。通过给予重组MERTK蛋白（GAS6在髓系细胞上表达的受体）中和GAS6，这种减少可以被逆转。此外，外源性补充GAS6可在体外增加小胶质细胞吞噬作用，并限制OIR中的病理性NV。我们的数据表明，通过调节GAS6-MERTK轴促进免疫细胞吞噬作用可能是治疗IR中病理性NV的一个潜在靶点。
