Caicedo Alejandro, Espinosa-Heidmann Diego G, Piña Yolanda, Hernandez Eleut P, Cousins Scott W
Bascom Palmer Eye Institute, University of Miami School of Medicine, 1638 NW 10th Avenue, Miami, FL 33136, USA.
Exp Eye Res. 2005 Jul;81(1):38-47. doi: 10.1016/j.exer.2005.01.013.
Inflammation is a major mechanism in the pathogenesis of age-related macular degeneration, the most important cause of blindness in the elderly. Previous studies have focused on the role of macrophages in regulating the growth of pathological new vessels over the retina, called choroidal neovascularization (CNV). However, no research has been done to evaluate the role of inflammation as a mechanism of vision loss and retinal degeneration in the retina underlying CNV. In other neuropathological conditions, hematogenous macrophages and/or resident microglia contribute to neurodegeneration. We have combined laser-induced CNV in mice and bone marrow transplantation with GFP-labeled bone marrow to determine the relative role of recruited blood-derived macrophages versus resident microglia in the retina associated with CNV. Using these chimeric mice, we have found that many GFP-labeled cells infiltrated the retina underlying CNV but not the retina unaffected by CNV. Immunostaining for the cell adhesion molecules VCAM 1, ICAM 1, and PECAM was strongly upregulated in retinal blood vessels under CNV. All GFP-labeled cells were immunoreactive for the macrophage marker F4/80. Most (70%) of the F4/80 immunoreactive cells were GFP-labeled under CNV. The density of resident microglia did not increase. Most GFP-labeled cells were found in close proximity to activated Muller cells. Depleting circulating macrophages with clodronic acid diminished the density of F4/80 immunoreactive cells as well as the density of pERK immunoreactive Muller cells in the retina under CNV. Thus, recruitment of blood-derived macrophages more than resident microglia seems to be associated with CNV.
炎症是年龄相关性黄斑变性发病机制中的主要机制，年龄相关性黄斑变性是老年人失明的最重要原因。以往的研究主要集中在巨噬细胞在调节视网膜上病理性新血管生长（即脉络膜新生血管形成，CNV）中的作用。然而，尚未有研究评估炎症作为CNV下方视网膜视力丧失和视网膜变性机制的作用。在其他神经病理条件下，血源性巨噬细胞和/或驻留小胶质细胞会导致神经变性。我们将小鼠激光诱导的CNV与骨髓移植以及绿色荧光蛋白（GFP）标记的骨髓相结合，以确定募集的血源性巨噬细胞与驻留小胶质细胞在与CNV相关的视网膜中的相对作用。利用这些嵌合小鼠，我们发现许多GFP标记的细胞浸润到CNV下方的视网膜中，但未浸润到未受CNV影响的视网膜中。在CNV下方的视网膜血管中，细胞粘附分子血管细胞粘附分子1（VCAM 1）、细胞间粘附分子1（ICAM 1）和血小板内皮细胞粘附分子（PECAM）的免疫染色强烈上调。所有GFP标记的细胞对巨噬细胞标志物F4/80均呈免疫反应性。在CNV下方，大多数（70%）F4/80免疫反应性细胞被GFP标记。驻留小胶质细胞的密度没有增加。大多数GFP标记的细胞位于活化的米勒细胞附近。用氯膦酸耗尽循环巨噬细胞可降低CNV下方视网膜中F4/80免疫反应性细胞的密度以及磷酸化细胞外信号调节激酶（pERK）免疫反应性米勒细胞的密度。因此，血源性巨噬细胞的募集而非驻留小胶质细胞的募集似乎与CNV相关。
