RAGE Regulates Immune Cell Infiltration and Angiogenesis in Choroidal Neovascularization

Abstract

PurposeRAGE regulates pro-inflammatory responses in diverse cells and tissues. This study has investigated if RAGE plays a role in immune cell mobilization and choroidal neovascular pathology that is associated with the neovascular form of age-related macular degeneration (nvAMD).MethodsRAGE null (RAGE−/−) mice and age-matched wild type (WT) control mice underwent laser photocoagulation to generate choroidal neovascularization (CNV) lesions which were then analyzed for morphology, S100B immunoreactivity and inflammatory cell infiltration. The chemotactic ability of bone marrow derived macrophages (BMDMs) towards S100B was investigated.ResultsRAGE expression was significantly increased in the retina during CNV of WT mice (p<0.001). RAGE−/− mice exhibited significantly reduced CNV lesion size when compared to WT controls (p<0.05). S100B mRNA was upregulated in the lasered WT retina but not RAGE−/− retina and S100B immunoreactivity was present within CNV lesions although levels were less when RAGE−/− mice were compared to WT controls. Activated microglia in lesions were considerably less abundant in RAGE−/− mice when compared to WT counterparts (p<0.001). A dose dependent chemotactic migration was observed in BMDMs from WT mice (p<0.05–0.01) but this was not apparent in cells isolated from RAGE−/− mice.ConclusionsRAGE-S100B interactions appear to play an important role in CNV lesion formation by regulating pro-inflammatory and angiogenic responses. This study highlights the role of RAGE in inflammation-mediated outer retinal pathology.

Role of the receptor for advanced glycation endproducts (RAGE) in retinal vasodegenerative pathology during diabetes in mice

“…This bimodal response according to the duration of diabetes may also reflect the altered expression levels of RAGE between 12 and 24 weeks. Further supporting evidence comes from Rage −/− mice subjected to laser-induced choroidal neovascularisation; these mice showed reduced lesion size alongside diminution of immune cell activation when compared with WT controls [ 46 ].…”

S100B Up-Regulates Macrophage Production of IL1β and CCL22 and Influences Severity of Retinal Inflammation

“…It has been suggested that T cell production of S100B, although less than that of astrocytes, may, when polarized in the immunological synapse, be sufficient to trigger macrophage activation [ 49 ]. Recently S100B has been shown to be up-regulated in the eye in response to laser photocoagulation which generated choroidal neovascularisation [ 50 ]. Thus it is likely that S100B is present in the retina in EAU at the concentrations we have shown in vitro are able to influence macrophage response.…”

Structural and molecular changes in the aging choroid: implications for age-related macular degeneration

“…RAGE may also contribute to the activation of immune cells in laser-induced CNV lesion in a mouse model of AMD. 74 Choriocapillary vascular dropout and changes to choroidal thickness in AMD Upon assessment of the mean choroidal blood flow in patients at risk for CNV development, Grunwald et al 75 discovered an association between decreased circulation within the choroid and increased risk for wet AMD. These data implicate ischemia in CNV formation, and provide evidence for the importance of decreased choroidal blood flow in disease progression.…”