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

Author:

Sheu Wayne Huey-Herng12,Lin Keng-Hung3ORCID,Wang Jun-Sing12ORCID,Lai De-Wei2ORCID,Lee Wen-Jane4ORCID,Lin Fu-Yu5,Chen Po-Hsun,Chen Cheng-Hsu6,Yeh Hsiang-Yu7,Wu Sheng-Mao2ORCID,Shen Chin-Chang8ORCID,Lee Maw-Rong9,Liu Shing-Hwa1011ORCID,Sheu Meei-Ling4212ORCID

Affiliation:

1. Division of Endocrinology and Metabolism, Department of Internal Medicine (W.H.-H.S., J.-S.W.), Taichung Veterans General Hospital, Taiwan.

2. Institute of Biomedical Sciences (W.H.-H.S., J.-S.W., D.-W.L., S.-M.W., M.-L.S.), National Chung Hsing University, Taichung, Taiwan.

3. Department of Ophthalmology (K.-H.L.), Taichung Veterans General Hospital, Taiwan.

4. Department of Medical Research (W.-J.L., M.-L.S.), Taichung Veterans General Hospital, Taiwan.

5. Department of Ophthalmology, Chiayi Branch Taichung Veterans General Hospital, Taiwan (F.-Y.L.).

6. Division of Nephrology, Department of Internal Medicine (C.-H.C.), Taichung Veterans General Hospital, Taiwan.

7. Department of Nutrition and Institute of Biomedical Nutrition, Hung-Kuang University, Taichung, Taiwan (H.-Y.Y.).

8. Institute of Nuclear Energy Research, Atomic Energy Council, Taoyuan, Taiwan (C.-C.S.).

9. Department of Chemistry (M.-R.L.), National Chung Hsing University, Taichung, Taiwan.

10. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei (S.-H.L.).

11. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan (S.-H.L.).

12. Rong Hsing Research Center for Translational Medicine (M.-L.S.), National Chung Hsing University, Taichung, Taiwan.

Abstract

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 Ɛ -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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine

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