Therapeutic Potential of Tpl2 (Tumor Progression Locus 2) Inhibition on Diabetic Vasculopathy Through the Blockage of the Inflammasome Complex

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 41; no. 1; p. e46
• Main Authors: Sheu, Wayne Huey-Herng, Lin, Keng-Hung, Wang, Jun-Sing, Lai, De-Wei, Lee, Wen-Jane, Lin, Fu-Yu, Chen, Po-Hsun, Chen, Cheng-Hsu, Yeh, Hsiang-Yu, Wu, Sheng-Mao, Shen, Chin-Chang, Lee, Maw-Rong, Liu, Shing-Hwa, Sheu, Meei-Ling
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.01.2021
• Subjects: Aged; Angiogenesis Inhibitors - pharmacology; Animals; Cells, Cultured; Cross-Sectional Studies; Databases, Factual; Diabetes Mellitus, Experimental - complications; Diabetes Mellitus, Experimental - diagnosis; Diabetes Mellitus, Experimental - enzymology; Diabetes Mellitus, Type 1 - complications; Diabetes Mellitus, Type 1 - diagnosis; Diabetes Mellitus, Type 1 - enzymology; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - enzymology; Diabetic Retinopathy - enzymology; Diabetic Retinopathy - etiology; Diabetic Retinopathy - pathology; Diabetic Retinopathy - prevention & control; Female; Humans; Inflammasomes - antagonists & inhibitors; Inflammasomes - metabolism; Male; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Mice; Mice, Inbred C57BL; Middle Aged; Pregnancy; Prospective Studies; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Retinal Neovascularization - enzymology; Retinal Neovascularization - etiology; Retinal Neovascularization - pathology; Retinal Neovascularization - prevention & control; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - enzymology; Retinal Pigment Epithelium - pathology; Signal Transduction; cytokine; tumor progression locus 2; Nε-carboxymethyllysine; inflammation; inflammasome; neovascularization; retinal pigment epithelium; diabetic retinopathy
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.120.315176

OBJECTIVE:Diabetic retinopathy, one of retinal vasculopathy, is characterized by retinal inflammation, vascular leakage, blood-retinal barrier breakdown, and neovascularization. However, the molecular mechanisms that contribute to diabetic retinopathy progression remain unclear. APPROACH AND RESULTS:Tpl2 (tumor progression locus 2) is a protein kinase implicated in inflammation and pathological vascular angiogenesis. N-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.