Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes.

Eimear M Byrne,María Llorián-Salvador,Timothy J Lyons,Mei Chen,Heping Xu

doi:10.3390/ijms222111876

Abstract

We have previously reported that inhibition of the Janus kinase 1 (JAK1) signaling ameliorates IL-17A-mediated blood-retinal barrier (BRB) dysfunction. Higher levels of IL-17A have been observed in the blood and intraocular fluids in patients with diabetic retinopathy (DR), in particular those with diabetic macular oedema. This study aimed to understand whether JAK1 inhibition could prevent BRB dysfunction in db/db mice, a model of type 2 diabetes (T2D). An in vitro study showed that high glucose treatment disrupted the junctional distribution of claudin-5 in bEnd3 cells and ZO-1 in ARPE19 cells and that tofacitinib citrate treatment prevented high glucose-mediated tight junction disruption. Albumin leakage, accompanied by increased levels of the phosphorylated form of JAK1 (pJAK1), was observed in three-month-old db/db mice. Treatment of two-and-a-half-month-old db/db mice with tofacitinib citrate for two weeks significantly reduced retinal albumin leakage and reduced pJAK1 expression. pJAK1 expression was also detected in human DR retina. Our results suggest that JAK1 inhibition can ameliorate BRB dysfunction in T2D, and JAK1 inhibitors such as tofacitinib citrate may be re-purposed for the management of diabetic macular oedema.

Highlights

463 million people are affected by diabetes, and the number is predicted to rise to 700 million by 2045 [1]
We investigated the effect of the Janus kinase 1 (JAK1) inhibitor tofacitinib citrate in Diabetic retinopathy (DR)-related Blood retinal barrier (BRB) leakage in a mouse model of T2DM, the BKS.Cg-Dock7m +/+Leprdb J mice
We found that phosphorylated form of JAK1 (pJAK1) expression was increased in the retina of db/db mice, and that treatment with the JAK1/2 inhibitor tofacitinib citrate significantly reduced BRB leakage in these mice

Summary

Introduction

463 million people are affected by diabetes, and the number is predicted to rise to 700 million by 2045 [1]. As the global prevalence of T2DM is increasing rapidly, the number of people experiencing vision loss from DMO is rising [2,3]. Current standards of care for DMO include the intraocular administration of anti-VEGF inhibitors, which have limited efficacy and require invasive repeat injections, or laser-photocoagulation, which can slow disease progression but cannot restore vision. Intravitreal injection of steroids or steroid implant (e.g., Ozurdex) have been used to treat DMO, for patients who do not respond to anti-VEGF therapy [5], steroid-induced complications such as cataract and glaucoma limit the suitability of steroid-based treatments.

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