Therapeutic Potential of Tpl2 (Tumor Progression Locus 2) Inhibition on Diabetic Vasculopathy through the Blockage of the Inflammasome Complex
Journal
Arteriosclerosis, Thrombosis, and Vascular Biology
Journal Volume
41
Journal Issue
1
Pages
E46-E62
Date Issued
2021
Author(s)
Sheu W.H.-H.
Lin K.-H.
Wang J.-S.
Lai D.-W.
Lee W.-J.
Lin F.-Y.
Chen P.-H.
Chen C.-H.
Yeh H.-Y.
Wu S.-M.
Shen C.-C.
Lee M.-R.
Sheu M.-L.
Abstract
OBJECTIVE: -carboxymethyllysine (CML) and inflammatory cytokines levels in human sera and in several diabetic murine models were detected by ELISA, whereas liquid chromatography-tandem mass spectrometry analysis was used for whole eye tissues. The CML and p-Tpl2 expressions on the human retinal pigment epithelium (RPE) cells were determined by immunofluorescence. Intravitreal injection of pharmacological inhibitor or NA (neutralizing antibody) was used in a diabetic rat model. Retinal leukostasis, optical coherence tomography, and H&E staining were used to observe pathological features. Sera of diabetic retinopathy patients had significantly increased CML levels that positively correlated with diabetic retinopathy severity and foveal thickness. CML and p-Tpl2 expressions also significantly increased in the RPE of both T1DM and T2DM diabetes animal models. Mechanistic studies on RPE revealed that CML-induced Tpl2 activation and NADPH oxidase, and inflammasome complex activation were all effectively attenuated by Tpl2 inhibition. Tpl2 inhibition by NA also effectively reduced inflammatory/angiogenic factors, retinal leukostasis in streptozotocin-induced diabetic rats, and RPE secretion of inflammatory cytokines. The attenuated release of angiogenic factors led to inhibited vascular abnormalities in the diabetic animal model. CONCLUSIONS: The inhibition of Tpl2 can block the inflammasome signaling pathway in RPE and has potential clinical and therapeutic implications in diabetes-associated retinal microvascular dysfunction.
SDGs
Publisher
Lippincott Williams and Wilkins
Type
journal article