Microglia in retinal angiogenesis and diabetic retinopathy

Abstract

Diabetic retinopathy has a high probability of causing visual impairment or blindness throughout the disease progression and is characterized by the growth of new blood vessels in the retina at an advanced, proliferative stage. Microglia are a resident immune population in the central nervous system, known to play a crucial role in regulating retinal angiogenesis in both physiological and pathological conditions, including diabetic retinopathy. Physiologically, they are located close to blood vessels and are essential for forming new blood vessels (neovascularization). In diabetic retinopathy, microglia become widely activated, showing a distinct polarization phenotype that leads to their accumulation around neovascular tufts. These activated microglia induce pathogenic angiogenesis through the secretion of various angiogenic factors and by regulating the status of endothelial cells. Interestingly, some subtypes of microglia simultaneously promote the regression of neovascularization tufts and normal angiogenesis in neovascularization lesions. Modulating the state of microglial activation to ameliorate neovascularization thus appears as a promising potential therapeutic approach for managing diabetic retinopathy.

Keywords: Angiogenesis; Diabetic retinopathy; Microglia modulation; Microglia state; Retinal neovascularization.

Fig. 1

The vasculature of the retina is regulated by a complex interplay of signaling pathways and the cell–cell interaction of different cell types. A Mature retinal vasculature. B Major cell signaling contributing to retinal vasculature development. C Overview of cell types supporting retinal neovessel formation. RPCP, radial peripapillary capillary plexus; SVP, superficial vascular plexus; IVP, intermediate vascular plexus; DVP, deep vascular plexus; NFL, nerve fiber layer; GCL, ganglion cell layers; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; TGFβ, transforming growth factor β; TGFβR, TGFβ receptor; HIF-1α, hypoxia-inducible factor 1α

Fig. 2

Distribution of microglia in the retina. A Microglia distribution and morphology in different layers of the retina in physiological conditions. B Microglia distribution and morphology at sprouting site in physiological condition. C Microglia distribution and morphology in different layers of the retina in diabetic retinopathy. D Microglia distribution at neovasculature tufts in diabetic retinopathy. GCL, ganglion cell layers; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; RPE, retinal pigment epithelium

Fig. 3

Molecular interactions between microglia and ECs. Microglia govern retinal vasculature development via interaction with ECs through receptor-ligand pairs or the secretion of soluble factors (shown in the panel to the left). In DR, microglia alter their ligand expression pattern or secrete angiogenic factors in order to influence pathogenic angiogenesis. Additionally, ECs alter the microglia phenotype as well as microglia polarization (shown in the panel to the right). sVEGFR1, soluble vascular endothelial growth factor receptor 1; VEGF-C, vascular endothelial growth factor C; VEGFR3, vascular endothelial growth factor receptor 3; Dll1, delta-like ligand 1; Dll4, delta-like ligand 4; CD95L, CD95 ligand; CXCR4, C-X-C chemokine receptor type 4; SDF-1, stromal cell derived factor 1; Spp1, secreted phosphoprotein 1; Gal3, galectin 3; Jag1, jagged1; CSF1R, colony stimulating factor 1 receptor; TNF-α, tumor necrosis factor alpha; LGALS3BP, lectin galactoside binding soluble 3 binding protein; RIP1/3, receptor-interacting serine/threonine-protein kinase 1/3; FGF2, fibroblast growth factor 2; IGF-1, insulin-like growth factor 1; NRP-1, neuropilin-1; FasL, Fas ligand; CD200R1, CD200 receptor 1