Corticosteroids reduce pathological angiogenesis yet compromise reparative vascular remodeling in a model of retinopathy

• 成果类型: Article
• 署名作者: Hata, Masayuki; Hata, Maki; Dejda, Agnieszka; Pilon, Frederique; Diaz-Marin, Roberto; Fournier, Frederik; Joyal, Jean- Sebastien; Cagnone, Gael; Ochi, Yotaro; Crespo-Garcia, Sergio; Wilson, Ariel M.; Sapieha, Przemyslaw
• 署名单位: Universite de Montreal; Universite de Montreal; Kyoto University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11533
• DOI: 10.1073/pnas.2411640121
• 发表日期: 2024-12-24
• 关键词: innate immunity; dexamethasone; mechanisms

摘要

Tissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system, this is observed through a predominantly innate immune response in retinal vascular diseases such as age- related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. Here, we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen- induced retinopathy, we report that dexamethasone, a broad- spectrum corticosteroid, suppresses initial formation of pathological preretinal neovascularization in early stages of disease, yet blunts reparative inflammation by impairing distinct myeloid cell populations, and hence reduces beneficial vascular remodeling in later stages of disease. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1- expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing lysozyme 2 are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus- faced properties of anti- inflammatory drugs should be considered, particularly in stages associated with persistent neovascularization.