Deletion of Tgfβ signal in activated microglia prolongs hypoxia‐induced retinal neovascularization enhancing Igf1 expression and retinal leukostasis. Issue 9 (25th May 2022)

• Record Type: Journal Article
• Authors: Usui‐Ouchi, Ayumi; Eade, Kevin; Giles, Sarah; Ideguchi, Yoichiro; Ouchi, Yasuo; Aguilar, Edith; Wei, Guoqin; Marra, Kyle V.; Berlow, Rebecca B.; Friedlander, Martin
• Is Part Of: Glia. Volume 70:Issue 9(2022)
• Page Start: 1762
• Page End: 1776
• Publication Date: 2022-05-25
• Subjects: a mouse model of oxygen‐induced retinopathy -- angiogenesis -- diabetic retinopathy -- hypoxia -- insulin like growth factor 1 -- ischemic retinopathy -- microglia -- neovascularization -- retinopathy of prematurity -- transforming growth factor; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.24218
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it is known that retinal microglia contribute to both physiological and pathological angiogenesis, the molecular mechanisms by which these glia regulate pathological NV have not been fully elucidated. In this study, we utilized a retinal microglia‐specific Transforming Growth Factor‐β (Tgfβ) receptor knock out mouse model and human iPSC‐derived microglia to examine the role of Tgfβ signaling in activated microglia during retinal NV. Using a tamoxifen‐inducible, microglia‐specific Tgfβ receptor type 2 (Tgfβr2) knockout mouse [Tgfβr2 KO (ΔMG)] we show that Tgfβ signaling in microglia actively represses leukostasis in retinal vessels. Furthermore, we show that Tgfβ signaling represses expression of the pro‐angiogenic factor, Insulin‐like growth factor 1 (Igf1), independent of Vegf regulation. Using the mouse model of oxygen‐induced retinopathy (OIR) we show that Tgfβ signaling in activated microglia plays a role in hypoxia‐induced NV where a loss in Tgfβ signaling microglia exacerbates and prolongs retinal NV in OIR. Using human iPSC‐derived microglia cells in an in vitro assay, we validate the role of Transforming Growth Factor‐β1 (Tgfβ1) in regulating Igf1 expression in hypoxic conditions. Finally, we show that Tgfβ signaling in microglia is essential for microglial homeostasis and that the disruption of Tgfβ signaling in microglia exacerbates retinal NV in OIR by promoting leukostasis and Igf1 expression. Main Points: Blocking Tgfβ signaling in retinal microglia induces activation and worsens OIR neovascularization by promoting leukostasis and Igf1 upregulation Tgfβ1 regulates Igf1 expression in microglia, rescuing hypoxia‐induced Igf1 upregulation in microglia