Abstract
BackgroundNeovascularization is a leading cause of visual loss typically associated with diabetic retinopathy (DR) and retinopathy of prematurity (ROP). Interleukin-17A (IL-17A) and endoplasmic reticulum (ER) stress both have been demonstrated to play a proangiogenic role in ischemic retinopathies. However, the relationship between IL-17A and ER stress in retinal neovascularization (RNV) under hypoxic conditions and its underlying mechanisms remain unclear.MethodsIn this study, oxygen-induced retinopathy (OIR) mice model was established and intravitreal injections were conducted. Changes of IL-17A and ER stress markers in retinas and cultured primary bone marrow derived macrophage (BMDM) under normoxic or hypoxic conditions were detected. Western blotting, Real-Time RT-PCR, Immunofluorescence assays were conducted to explore the roles and relationship of IL-17A and ER stress in RNV, as well as its underlying mechanisms.ResultsCompared to that in normal controls, IL-17A and ER stress markers were all remarkably increased under hypoxic conditions both in vivo and in vitro. Neutralization or knock out of IL-17A decreased ER stress. ER stress inhibitor 4-phenylbutyrate (4-PBA), attenuated the production of IL-17A, suggesting a positive feedback loop between IL-17A and ER stress. Inhibition of IL-17A or ER stress decreased areas of nonperfusion and neovascularization in OIR retinas. As TXNIP/NLRP3 pathway activation has been demonstrated to be involved in increased retinal vascular permeability of ischemic retinopathy, we observed that TXNIP/NLRP3 pathway mediated in the interaction between IL-17A and ER stress under hypoxic conditions.ConclusionThe interplay between IL-17A and ER stress contributes to RNV in macrophages via modulation of TXNIP/NLRP3 signaling pathway under hypoxic conditions. The feedback loops may become an innovative and multiple pharmacological therapeutic target for ischemic retinopathy.
Highlights
Retinal neovascularization (RNV) is a primary cause of blindness in several vision-threatening diseases, such as diabetic retinopathy (DR), retinopathy of prematurityWang et al Cell Biosci (2021) 11:82(ROP), central retinal vein occlusion (CRVO), age-related macular degeneration (AMD) and neovascular glaucoma (NVG), which occurs when retinal blood supply is insufficient to meet the metabolic demands under the stimulation of ischemia or hypoxic conditions [1,2,3]
Alterations of IL‐17A and endoplasmic reticulum (ER) stress markers in oxygen-induced retinopathy (OIR) retinas and macrophages under hypoxic conditions IL-17A and ER stress play important roles in promoting angiogenesis of ischemic diseases [15, 18, 19]. To evaluate their involvement in the macrophages of ischemic retinopathy, we examined the expression levels of IL-17A and ER stress markers in OIR retinas and in macrophages under hypoxia
(See figure on page.) Fig. 1 Hypoxia-induced changes of IL-17A and ER stress markers in retinas and macrophages. a Western blotting analysis of Glucose-regulated 78 kDa protein (GRP78), Activating transcription factor 4 (ATF-4) and IL-17A protein levels at P12, P15, P17, P21 in retinas of OIR mice compared with their age-matched controls. b Immunofluorescent staining of F4/80 and ATF-4, GRP78, IL-17A on representative sections of retinas from P17 OIR mice and normal controls
Summary
Retinal neovascularization (RNV) is a primary cause of blindness in several vision-threatening diseases, such as diabetic retinopathy (DR), retinopathy of prematurityWang et al Cell Biosci (2021) 11:82(ROP), central retinal vein occlusion (CRVO), age-related macular degeneration (AMD) and neovascular glaucoma (NVG), which occurs when retinal blood supply is insufficient to meet the metabolic demands under the stimulation of ischemia or hypoxic conditions [1,2,3]. Retinal neovascularization (RNV) is a primary cause of blindness in several vision-threatening diseases, such as diabetic retinopathy (DR), retinopathy of prematurity. Anti-vascular endothelial growth factor (anti-VEGF) agents and laser photocoagulation are the most effective therapies for RNV [4]. Retinal inflammation following ischemic retinopathy is characterized by activated inflammatory cell accumulation and activation, including Müller cells and macrophages [16]. They can release inflammatory factors, such as IL-17A [17], IL-1β, TNF-α and MCP-1 [7, 16]. The relationship between IL-17A and ER stress in retinal neovascularization (RNV) under hypoxic conditions and its underlying mechanisms remain unclear
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