Abstract
Blood–retinal barrier (BRB) dysfunction underlies macular oedema in many sight-threatening conditions, including diabetic macular oedema, neovascular age-related macular degeneration and uveoretinitis. Inflammation plays an important role in BRB dysfunction. This study aimed to understand the role of the inflammatory cytokine IL-17A in BRB dysfunction and the mechanism involved. Human retinal pigment epithelial (RPE) cell line ARPE19 and murine brain endothelial line bEnd.3 were cultured on transwell membranes to model the outer BRB and inner BRB, respectively. IL-17A treatment (3 days in bEnd.3 cells and 6 days in ARPE19 cells) disrupted the distribution of claudin-5 in bEnd.3 cells and ZO-1 in ARPE19 cells, reduced the transepithelial/transendothelial electrical resistance (TEER) and increased permeability to FITC-tracers in vitro. Intravitreal (20 ng/1 μL/eye) or intravenous (20 ng/g) injection of recombinant IL-17A induced retinal albumin leakage within 48 h in C57BL/6J mice. Mechanistically, IL-17A induced Janus kinase 1 (JAK1) phosphorylation in bEnd.3 but not ARPE19 cells. Blocking JAK1 with Tofacitinib prevented IL-17A-mediated claudin-5 dysmorphia in bEnd.3 cells and reduced albumin leakage in IL-17A-treated mice. Our results suggest that IL-17A can damage the BRB through the activating the JAK1 signaling pathway, and targeting this pathway may be a novel approach to treat inflammation-induced macular oedema.
Highlights
Our results suggest that the JAK/STAT pathway is an attractive therapeutic target for IL-17A-induced macular oedema
Measurement of trans-epithelial electrical resistance (TEER) in bEnd3 cells cultured in the transwell membrane showed that 72 h of treatment with IL-17A significantly reduced transendothelial electrical resistance (TEER) (Figure 1B)
We found that 3–6 days of treatment with IL-17A could increase IL-6 but not VEGF production in bEnd.3 cells, indicating that IL-17A can active the JAK/STAT pathway directly and indirectly under chronic disease conditions, such as in DR and uveoretinitis
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The blood–retinal barrier (BRB) segregates the neuroretina from the periphery, thereby protecting the retina from exogenous pathogen invasion and systemic inflammatory disturbances. The BRB consists of the inner BRB (iBRB), i.e., tight junctions between retinal endothelial cells and outer BRB (oBRB), i.e., tight junctions between retinal pigment epithelial (RPE) cells. BRB dysfunction may result in the infiltration of circulating immune cells and the leakage of fluid into the neuroretina, causing retinal oedema. BRB dysfunction underpins many sight-threatening retinal diseases, such as diabetic macular oedema (DMO) [1], age-related macular degeneration (AMD) [2,3] and uveitis [4,5]
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