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Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: a novel inhibitory effect of minocycline

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Abstract

Objective and design

Chronic low-grade inflammation occurs in diabetic retinopathy (DR), but the underlying mechanism(s) remains (remain) unclear. NLRP3 inflammasome activation is involved in several other inflammatory diseases. Thus, we investigated the role of the NLRP3 inflammasome signaling pathway in the pathogenesis of DR.

Methods

Diabetes was induced in rats by streptozotocin treatment for 8 weeks. They were treated with NLRP3 shRNA or minocycline during the last 4 weeks. High glucose-exposed human retinal microvascular endothelial cells (HRMECs) were co-incubated with antioxidants or subjected to TXNIP or NLRP3 shRNA interference.

Results

In high glucose-exposed HRMECs and retinas of diabetic rats, mRNA and protein expression of NLRP3, ASC, and proinflammatory cytokines were induced significantly by hyperglycemia. Upregulated interleukin (IL)-1β maturation, IL-18 secretion, and caspase-1 cleavage were also observed with increased cell apoptosis and retinal vascular permeability, compared with the control group. NLRP3 silencing blocked these effects in the rat model and HRMECs, confirming that inflammasome activation contributed to inflammation in DR. TXNIP expression was increased by reactive oxygen species (ROS) overproduction in animal and cell models, whereas antioxidant addition or TXNIP silencing blocked IL-1β and IL-18 secretion in high glucose-exposed HRMECs, indicating that the ROS–TXNIP pathway mediates NLRP3 inflammasome activation. Minocycline significantly downregulated ROS generation and reduced TXNIP expression, subsequently inhibited NLRP3 activation, and further decreased inflammatory factors, which were associated with a decrease in retinal vascular permeability and cell apoptosis.

Conclusions

Together, our data suggest that the TXNIP/NLRP3 pathway is a potential therapeutic target for the treatment of DR, and the use of minocycline specifically for such therapy may be a new avenue of investigation in inflammatory disease.

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References

  1. Ding J, Wong TY. Current epidemiology of diabetic retinopathy and diabetic macular edema. Curr Diab Rep. 2012;12:346–54.

    Article  PubMed  Google Scholar 

  2. El-Asrar AM. Role of inflammation in the pathogenesis of diabetic retinopathy. Middle East Afr J Ophthalmol. 2012;19:70–4.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kowluru RA, Odenbach S. Role of interleukin-1beta in the pathogenesis of diabetic retinopathy. Br J Ophthalmol. 2004;88:1343–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.

    Article  CAS  PubMed  Google Scholar 

  5. Cassel SL, Joly S, Sutterwala FS. The NLRP3 inflammasome: a sensor of immune danger signals. Semin Immunol. 2009;21:194–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Leavy O. Inflammasome: turning on and off NLRP3. Nat Rev Immunol. 2013;13:1.

    Article  PubMed  Google Scholar 

  7. Michaudel C, Couturier-Maillard A, Chenuet P, et al. Inflammasome, IL-1 and inflammation in ozone-induced lung injury. Am J Clin Exp Immunol. 2016;5:33–40.

    PubMed  PubMed Central  Google Scholar 

  8. Perrone L, Devi TS, Hosoya K, Terasaki T, Singh LP. Thioredoxin interacting protein (TXNIP) induces inflammation through chromatin modification in retinal capillary endothelial cells under diabetic conditions. J Cell Physiol. 2009;221:262–72.

    Article  CAS  PubMed  Google Scholar 

  9. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2010;11:136–40.

    Article  CAS  PubMed  Google Scholar 

  10. Perrone L, Devi TS, Hosoya KI, Terasaki T, Singh LP. Inhibition of TXNIP expression in vivo blocks early pathologies of diabetic retinopathy. Cell Death Dis. 2010;1:e65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li C, Yuan K, Schluesener H. Impact of minocycline on neurodegenerative diseases in rodents: a meta-analysis. Rev Neurosci. 2013;24:553–62.

    Article  PubMed  Google Scholar 

  12. Krady JK, Basu A, Allen CM, Xu Y, LaNoue KF, Gardner TW, et al. Minocycline reduces proinflammatory cytokine expression, microglial activation, and caspase-3 activation in a rodent model of diabetic retinopathy. Diabetes. 2005;54:1559–65.

    Article  CAS  PubMed  Google Scholar 

  13. Zheng Z, Chen H, Li J, Li T, Zheng B, Zheng Y, et al. Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes. 2012;61:217–28.

    Article  CAS  PubMed  Google Scholar 

  14. Leal EC, Martins J, Voabil P, Liberal J, Chiavaroli C, Bauer J, et al. Calcium dobesilate inhibits the alterations in tight junction proteins and leukocyte adhesion to retinal endothelial cells induced by diabetes. Diabetes. 2010;59:2637–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kingsbury SR, Conaghan PG, McDermott MF. The role of the NLRP3 inflammasome in gout. J Inflamm Res. 2011;4:39–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee HM, Kim JJ, Kim HJ, Shong M, Ku BJ, Jo EK. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013;62:194–204.

    Article  CAS  PubMed  Google Scholar 

  17. Al-Shabrawey M, Zhang W, McDonald D. Diabetic retinopathy: mechanism, diagnosis, prevention, and treatment. BioMed Res Int. 2015;2015:854593.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sagulenko V, Thygesen SJ, Sester DP, et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ. 2013;20:1149–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Heid ME, Keyel PA, Kamga C, Shiva S, Watkins SC, Salter RD. Mitochondrial reactive oxygen species induces NLRP3-dependent lysosomal damage and inflammasome activation. J Immunol. 2013;191:5230–8.

    Article  CAS  PubMed  Google Scholar 

  21. Tschopp J, Schroder K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat Rev Immunol. 2010;10:210–5.

    Article  CAS  PubMed  Google Scholar 

  22. Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat Immunol. 2009;11:136–40.

    Article  PubMed  Google Scholar 

  23. Devi TS, Hosoya K-I, Terasaki T, Singh LP. Critical role of TXNIP in oxidative stress. DNA damage and retinal pericyte apoptosis under high glucose: Implications for diabetic retinopathy. Experimental cell research; 2013.

    Google Scholar 

  24. Szeto GL, Pomerantz JL, Graham DR, Clements JE. Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. J Biol Chem. 2011;286:11275–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Giuliani F, Hader W, Yong VW. Minocycline attenuates T cell and microglia activity to impair cytokine production in T cell–microglia interaction. J Leukoc Biol. 2005;78:135–43.

    Article  CAS  PubMed  Google Scholar 

  26. Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW. Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem. 2005;94:819–27.

    Article  CAS  PubMed  Google Scholar 

  27. Plane JM, Shen Y, Pleasure DE, Deng W. Prospects for minocycline neuroprotection. Arch Neurol. 2010;67:1442–8.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bhatt LK, Addepalli V. Attenuation of diabetic retinopathy by enhanced inhibition of MMP-2 and MMP-9 using aspirin and minocycline in streptozotocin-diabetic rats. Am J Transl Res. 2010;2:181–9.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Nature Science Foundation of China (81271032) and the Shanghai Nature Science Foundation (No. 14ZR1433600).

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Authors and Affiliations

  1. Department of Ophthalmology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200080, China

    Wei Chen, Minjie Zhao, Shuzhi Zhao, Qianyi Lu, Chen Zou, Xun Xu, Zhi Zheng & Qinghua Qiu

  2. Department of Ophthalmology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China

    Wei Chen & Huaijin Guan

  3. Department of Ophthalmology, Lishui People’s Hospital, Lishui, 323000, Zhejiang, China

    Lisha Ni

  4. Department of Ophthalmology, Anhui Provincial Hospital, Hefei, China

    Li Lu

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  1. Wei Chen
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  2. Minjie Zhao
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Correspondence to Zhi Zheng or Qinghua Qiu.

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Responsible Editor: Graham R. Wallace.

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Chen, W., Zhao, M., Zhao, S. et al. Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: a novel inhibitory effect of minocycline. Inflamm. Res. 66, 157–166 (2017). https://doi.org/10.1007/s00011-016-1002-6

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  • DOI: https://doi.org/10.1007/s00011-016-1002-6

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