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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 52; p. e2411640121
• Main Authors: Hata, Masayuki, Hata, Maki, Dejda, Agnieszka, Pilon, Frédérique, Diaz-Marin, Roberto, Fournier, Frédérik, Joyal, Jean-Sebastien, Cagnone, Gael, Ochi, Yotaro, Crespo-Garcia, Sergio, Wilson, Ariel M., Sapieha, Przemyslaw
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.12.2024
• Subjects: Adrenal Cortex Hormones - pharmacology; Adrenal Cortex Hormones - therapeutic use; Age; Age related diseases; Angiogenesis; Animals; Anti-inflammatory agents; Biological Sciences; Blood vessels; Central nervous system; Chemokine receptors; Corticoids; Corticosteroids; CX3C Chemokine Receptor 1 - genetics; CX3C Chemokine Receptor 1 - metabolism; Damage; Dexamethasone; Dexamethasone - pharmacology; Diabetes mellitus; Disease Models, Animal; Eye diseases; Homeostasis; Immune response; Immune system; Immunity, Innate - drug effects; Immunosuppressive agents; Inflammation; Inflammation - drug therapy; Inflammation - pathology; Innate immunity; Lysozyme; Macular degeneration; Mice; Mice, Inbred C57BL; Microglia; Microglia - drug effects; Microglia - metabolism; Microglia - pathology; Muramidase - metabolism; Myeloid cells; Myeloid Cells - drug effects; Myeloid Cells - metabolism; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Oxygen - metabolism; Population genetics; Regression models; Retina - drug effects; Retina - metabolism; Retina - pathology; Retinal Neovascularization - drug therapy; Retinal Neovascularization - metabolism; Retinal Neovascularization - pathology; Retinal Vessels - drug effects; Retinal Vessels - metabolism; Retinal Vessels - pathology; Retinopathy; Steroids; Vascular diseases; Vascular Remodeling - drug effects; Vascularization; dexamethasone; inflammation; retina; retinopathy; angiogenesis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2411640121

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.