Increased expression of TSPO-VDAC complex is correlated with NLRP3 inflammasome activation in diabetic retinopathy

Guo,Yue; Sun,Zhongcui; Wang,Ling; Jiang,Rui; Shu,Qinmeng; Xu,Gezhi

doi:10.3892/mmr.2022.12869

Increased expression of TSPO-VDAC complex is correlated with NLRP3 inflammasome activation in diabetic retinopathy

Authors:
- Yue Guo
- Zhongcui Sun
- Ling Wang
- Rui Jiang
- Qinmeng Shu
- Gezhi Xu
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Affiliations: Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai 200031, P.R. China
Published online on: October 5, 2022 https://doi.org/10.3892/mmr.2022.12869
Article Number: 353

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Abstract

The present study aimed to investigate the level of translocator protein (TSPO) and its correlation with different inflammatory cytokines in diabetic retinopathy (DR) patients. Peripheral blood samples were obtained from 54 DR patients and 22 age-related cataract (ARC) patients. The mRNA expression of TSPO, voltage-dependent anion channel (VDAC), apoptosis-associated speck like protein with a caspase recruitment domain (ASC), NOD-like receptors pyrin domain-containing 3 (NLRP3) and caspase-1 were examined by reverse transcription-quantitative PCR. Interleukin-1β and interleukin-18 levels were detected by enzyme-linked immunosorbent assay. The mRNA levels of TSPO, VDAC, ASC, NLRP3 and capase-1, the protein levels of IL-β and IL-18 were all significantly higher in the DR group compared with those in the ARC group. The expression levels of those aforementioned cytokines/proteins were more significantly higher in the subgroup of active proliferative DR (PDR) compared with those in the inactive PDR group (P<0.05). Significant positive correlations between TSPO/VDAC complex and ASC, NLRP3, capase-1, IL-β and IL-18 were found in DR patients. These outcomes suggested that TSPO/VDAC complex and NLRP3 inflammasomes may play an important role in the development and progression of DR.

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1	Semeraro F, Morescalchi F, Cancarini A, Russo A, Rezzola S and Costagliola C: Diabetic retinopathy, a vascular and inflammatory disease: Therapeutic implications. Diabetes Metab. 45:517–527. 2019. View Article : Google Scholar : PubMed/NCBI
2	Kowluru RA, Kowluru A, Mishra M and Kumar B: Oxidative stress and epigenetic modifications in the pathogenesis of diabetic retinopathy. Prog Retin Eye Res. 48:40–61. 2015. View Article : Google Scholar : PubMed/NCBI
3	Simó-Servat O, Simó R and Hernández C: Circulating biomarkers of diabetic retinopathy: An overview based on physiopathology. J Diabetes Res. 2016:52637982016. View Article : Google Scholar : PubMed/NCBI
4	Figueras-Roca M, Molins B, Sala-Puigdollers A, Matas J, Vinagre I, Ríos J and Adán A: Peripheral blood metabolic and inflammatory factors as biomarkers to ocular findings in diabetic macular edema. PLoS One. 12:e01738652017. View Article : Google Scholar : PubMed/NCBI
5	Tang J and Kern TS: Inflammation in diabetic retinopathy. Prog Retin Eye Res. 30:343–358. 2011. View Article : Google Scholar : PubMed/NCBI
6	Zeiner J, Loukovaara S, Losenkova K, Zuccarini M, Korhonen AM, Lehti K, Kauppinen A, Kaarniranta K, Müller CE, Jalkanen S and Yegutkin GG: Soluble and membrane-bound adenylate kinase and nucleotidases augment ATP-mediated inflammation in diabetic retinopathy eyes with vitreous hemorrhage. J Mol Med (Berl). 97:341–354. 2019. View Article : Google Scholar : PubMed/NCBI
7	Mishra M, Lillvis J, Seyoum B and Kowluru RA: Peripheral blood mitochondrial DNA damage as a potential noninvasive biomarker of diabetic retinopathy. Invest Ophthalmol Vis Sci. 57:4035–4044. 2016. View Article : Google Scholar : PubMed/NCBI
8	Blake R and Trounce IA: Mitochondrial dysfunction and complications associated with diabetes. Biochim Biophys Acta. 1840:1404–1412. 2014. View Article : Google Scholar : PubMed/NCBI
9	Ilkan Z and Akar FG: The mitochondrial translocator protein and the emerging link between oxidative stress and arrhythmias in the diabetic heart. Front Physiol. 9:15182018. View Article : Google Scholar : PubMed/NCBI
10	Shoshan-Barmatz V, Pittala S and Mizrachi D: VDAC1 and the TSPO: Expression, interactions, and associated functions in health and disease states. Int J Mol Sci. 20:33482019. View Article : Google Scholar : PubMed/NCBI
11	Gatliff J, East D, Crosby J, Abeti R, Harvey R, Craigen W, Parker P and Campanella M: TSPO interacts with VDAC1 and triggers a ROS-mediated inhibition of mitochondrial quality control. Autophagy. 10:2279–2296. 2014. View Article : Google Scholar : PubMed/NCBI
12	Zhou R, Yazdi AS, Menu P and Tschopp J: A role for mitochondria in NLRP3 inflammasome activation. Nature. 469:221–225. 2011. View Article : Google Scholar : PubMed/NCBI
13	Afonina IS, Zhong Z, Karin M and Beyaert R: Limiting inflammation-the negative regulation of NF-κB and the NLRP3 inflammasome. Nat Immunol. 18:861–869. 2017. View Article : Google Scholar : PubMed/NCBI
14	Swanson KV, Deng M and Ting JPY: The NLRP3 inflammasome: Molecular activation and regulation to therapeutics. Nat Rev Immunol. 19:477–489. 2019. View Article : Google Scholar : PubMed/NCBI
15	Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, Pasquale LR, Thieme H, Iwamoto MA, Park JE, et al: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 331:1480–1487. 1994. View Article : Google Scholar : PubMed/NCBI
16	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
17	Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, et al: Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 12:222–230. 2011. View Article : Google Scholar : PubMed/NCBI
18	Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, et al: Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 36:401–414. 2012. View Article : Google Scholar : PubMed/NCBI
19	Lv Q, Xu D, Ma J, Wang Y, Yang X, Zhao P, Ma L, Li Z, Yang W, Liu X, et al: Uric acid drives intestinal barrier dysfunction through TSPO-mediated NLRP3 inflammasome activation. Inflamm Res. 70:127–137. 2021. View Article : Google Scholar : PubMed/NCBI
20	Feng H, Liu Y, Zhang R, Liang Y, Sun L, Lan N and Ma B: TSPO ligands PK11195 and midazolam reduce NLRP3 inflammasome activation and proinflammatory cytokine release in BV-2 cells. Front Cell Neurosci. 14:5444312020. View Article : Google Scholar : PubMed/NCBI
21	Franceschi C, Garagnani P, Parini P, Giuliani C and Santoro A: Inflammaging: A new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 14:576–590. 2018. View Article : Google Scholar : PubMed/NCBI
22	Wolf A, Herb M, Schramm M and Langmann T: The TSPO-NOX1 axis controls phagocyte-triggered pathological angiogenesis in the eye. Nat Commun. 11:27092020. View Article : Google Scholar : PubMed/NCBI
23	Chen H, Zhang X, Liao N, Mi L, Peng Y, Liu B, Zhang S and Wen F: Enhanced expression of NLRP3 inflammasome-related inflammation in diabetic retinopathy. Invest Ophthalmol Vis Sci. 59:978–985. 2018. View Article : Google Scholar : PubMed/NCBI
24	Wan Z, Fan Y, Liu X, Xue J, Han Z, Zhu C and Wang X: NLRP3 inflammasome promotes diabetes-induced endothelial inflammation and atherosclerosis. Diabetes Metab Syndr Obes. 12:1931–1942. 2019. View Article : Google Scholar : PubMed/NCBI
25	Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin XJ, Wong J, Ding S, Seki E, Schnabl B, et al: New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature. 560:198–203. 2018. View Article : Google Scholar : PubMed/NCBI
26	Song Z, Sun M, Zhou F, Huang F, Qu J and Chen D: Increased intravitreous interleukin-18 correlated to vascular endothelial growth factor in patients with active proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 252:1229–1234. 2014. View Article : Google Scholar : PubMed/NCBI