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

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...

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Autores principales:	Eimear M. Byrne, María Llorián-Salvador, Timothy J. Lyons, Mei Chen, Heping Xu
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	JAK1 diabetes JAK/STAT retina inflammation macular edema Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/87449f3a925a48d2b1438066aeb4b0e7
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spelling	oai:doaj.org-article:87449f3a925a48d2b1438066aeb4b0e72021-11-11T17:17:54ZTofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes10.3390/ijms2221118761422-00671661-6596https://doaj.org/article/87449f3a925a48d2b1438066aeb4b0e72021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11876https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067We 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.Eimear M. ByrneMaría Llorián-SalvadorTimothy J. LyonsMei ChenHeping XuMDPI AGarticleJAK1diabetesJAK/STATretinainflammationmacular edemaBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11876, p 11876 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	JAK1 diabetes JAK/STAT retina inflammation macular edema Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	JAK1 diabetes JAK/STAT retina inflammation macular edema Biology (General) QH301-705.5 Chemistry QD1-999 Eimear M. Byrne María Llorián-Salvador Timothy J. Lyons Mei Chen Heping Xu Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes
description	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.
format	article
author	Eimear M. Byrne María Llorián-Salvador Timothy J. Lyons Mei Chen Heping Xu
author_facet	Eimear M. Byrne María Llorián-Salvador Timothy J. Lyons Mei Chen Heping Xu
author_sort	Eimear M. Byrne
title	Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes
title_short	Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes
title_full	Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes
title_fullStr	Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes
title_full_unstemmed	Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes
title_sort	tofacitinib ameliorates retinal vascular leakage in a murine model of diabetic retinopathy with type 2 diabetes
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/87449f3a925a48d2b1438066aeb4b0e7
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Tofacitinib Ameliorates Retinal Vascular Leakage in a Murine Model of Diabetic Retinopathy with Type 2 Diabetes

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