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.