Blocking the interaction between interleukin-17A and endoplasmic reticulum stress in macrophage attenuates retinal neovascularization in oxygen-induced retinopathy

Abstract

Background Neovascularization 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. Methods In 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. Results Compared 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. Conclusion The 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.

Salubrinal Ameliorates Inflammation and Neovascularization via the Caspase 3/Enos Signaling in an Alkaline-Induced Rat Corneal Neovascularization Model

“…Activation of the ER stress pathway may contribute to angiogenesis and inflammation in retinal vascular endothelial cells in a high-dose glucose-induced diabetic retinopathy model [ 25 ]. Similarly, Wang et al demonstrated the ER stress pathway in the retinal neovascular process as a novel target mechanism for anti-inflammatory and antivascular therapy [ 26 ]. To the best of our knowledge, this is the first study to investigate the ER stress pathway in a corneal alkaline-burn model.…”

Pharmacological Inhibition of Glutaminase 1 Attenuates Alkali-Induced Corneal Neovascularization by Modulating Macrophages

“…During development and tissue healing or regeneration, M2-polarized macrophages stimulate angiogenesis and facilitate tissue remodeling by secreting a number of proteases and growth factors [ 36 , 37 ]. An increasing body of evidence revealed that the recruitment and M2 polarization of macrophages are closely associated with multiple models of ocular neovascularization, such as oxygen-induced retinopathy (OIR) [ 38 , 39 ] and choroidal neovascularization (CNV) [ 4 , 40 , 41 ]. However, the specific roles of M2 macrophages in CoNV are not defined.…”

Systemic Cytokines in Retinopathy of Prematurity

“…It also plays a crucial role in intraocular inflammation [ 44 ]. In a mouse OIR model, blocking IL-17 decreased the retinal areas of nonperfusion and neovascularization [ 45 ]. However, low serum IL-17 levels at birth have been noted in preterm infants who later developed severe ROP [ 27 ].…”