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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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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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