Anti-IL17A Halts the Onset of Diabetic Retinopathy in Type I and II Diabetic Mice

Abstract

There are ~463 million diabetics worldwide, and more than half have diabetic retinopathy. Yet, treatments are still lacking for non-proliferative diabetic retinopathy. We and others previously provided evidence that Interleukin-17A (IL-17A) plays a pivotal role in non-proliferative diabetic retinopathy. However, all murine studies used Type I diabetes models. Hence, it was the aim of this study to determine if IL-17A induces non-proliferative diabetic retinopathy in Type II diabetic mice, as identified for Type I diabetes. While examining the efficacy of anti-IL-17A as a potential therapeutic in a short-term Type I and a long-term Type II diabetes model; using different routes of administration of anti-IL-17A treatments. Retinal inflammation was significantly decreased (p < 0.05) after Type I-diabetic mice received 1 intravitreal injection, and Type II-diabetic mice received seven intraperitoneal injections of anti-IL-17A. Further, vascular tight junction protein Zonula Occludens-1 (ZO-1) was significantly decreased in both Type I and II diabetic mice, which was significantly increased when mice received anti-IL-17A injections (p < 0.05). Similarly, tight junction protein Occludin degradation was halted in Type II diabetic mice that received anti-IL-17A treatments. Finally, retinal capillary degeneration was halted 6 months after diabetes was confirmed in Type II-diabetic mice that received weekly intraperitoneal injections of anti-IL-17A. These findings provide evidence that IL-17A plays a pivotal role in non-proliferative diabetic retinopathy in Type II diabetic mice, and suggests that anti-IL-17A could be a good therapeutic candidate for non-proliferative diabetic retinopathy.

Roles of interleukins (interleukin-18 and interleukin-17a) and transforming growth factor-beta markers in the pathogenesis of diabetic kidney diseases

“…(2022)[ 20 ] showed that IL-18 was considered a predictive biomarker in screening patients with kidney diseases (sensitivity 74% and specificity 82%) (Zhou et al ., 2023). [ 23 ]…”

Unveiling the molecular complexity of proliferative diabetic retinopathy through scRNA-seq, AlphaFold 2, and machine learning

“…Current treatments such as panretinal photocoagulation have limitations, including potential adverse effects on visual acuity (29). Novel approaches such as CD40-TRAF6 inhibition (30) and anti-IL17A therapy (31) show promise in mouse models but require further clinical validation. These limitations underscore the pressing need for more effective and precise therapeutic strategies.…”

Cell and molecular targeted therapies for diabetic retinopathy

“…Few of the Th17 cells in the circulation were also shown to adhere to the retinal vasculature, thus predicting to be participating in the breakdown of BRB. The IL-17A secreted into the retina binds to their receptors on Müller glial cells and photoreceptors, activating the NF-κβ pathway, Fas-associated death domain (FADD) retinal vascular endothelial cell death, as well as ERK-dependent oxidative stress resulting in retinal vascular impairment and BRB dysfunction ( 26 , 27 ). The role of photoreceptor cells in maintaining inner BRB in the diabetic retina is another emerging field.…”

“…In PDR, vitreous IL-17A levels are associated with IL-10, IL-22, and TNFα levels in the aqueous humor and vitreous ( 171 ). Administering intravitreal or intraperitoneal injections of anti-IL-17A antibody or anti-IL-17RA antibody to type 1 and type 2 diabetic mice significantly reduces DR pathologies, including Müller cell dysfunction, leukostasis, leakage, downregulation of tight junction proteins, and ganglion cell apoptosis in the retina ( 27 , 172 ).…”