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Relationship between IL-22 and IL-22BP in diabetic cognitive dysfunction

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Abstract

Background

CD4 + T helper (Th)22 cells play a regulatory role in autoimmune diseases such as type 1 diabetes mellitus. The Th22-related cytokine interleukin (IL)-22, the expression of which is increased in diabetes mellitus (DM), can act as a neurotrophic factor to protect neurons from apoptosis. Paradoxically, neuronal apoptosis and learning and memory decline occur in DM. In this study, we investigated the relationship between IL-22 and its receptors IL-22Rα1 and IL-22 binding protein (IL-22BP, a soluble inhibitor of IL-22) in diabetic encephalopathy (DE) and the effects of IL-22 on hippocampal neurons, learning and memory.

Methods

A C57BL/6 mouse model of diabetes was constructed by intraperitoneal injection of streptozotocin. The mice were randomly divided into 4 groups: the control group, diabetes group, diabetes + recombinantIL-22 (rIL-22) group and diabetes + IL-22BP group. The Morris water maze test was used to evaluate learning and memory, the expression of IL-22 was measured by ELISA, and Evans Blue staining was used to evaluate blood–brain barrier permeability. Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to measure the mRNA expression of IL-22 and IL-22Rα1 in the hippocampus. The morphology and number of hippocampal neurons were assessed by Nissl staining, and TUNEL staining was used to detect hippocampal neuronal apoptosis. Immunofluorescence was used to analyze IL-22Rα1 expression and localization in hippocampus, and Western blotting was used to evaluate the expression of IL-22, IL-22Rα1, IL-22BP, and the apoptosis related proteins Caspase-3 and C-caspase-3.

Results

Compared with those in the control group, mice in the diabetes group showed cognitive decline; apoptosis of hippocampal neurons; increased expression of hippocampal Caspase-3, C-Caspase-3, IL-22, IL-22Rα1, and IL-22BP; and a decreased IL-22/IL-22BP ratio. Learning and memory were improved, neuronal apoptosis was attenuated, IL-22Rα1 expression and the IL-22/IL-22BP ratio were increased, and caspase-3 and C-caspase-3 expression was decreased in the rIL-22-treated group compared with the diabetes group. IL-22BP treatment aggravated diabetic cognitive dysfunction and pathological alterations in the hippocampus, decreased the IL-22/IL-22BP ratio, and increased the expression of caspase-3 and C-caspase-3 in mice with diabetes.

Conclusion

A decrease in the IL-22/IL-22BP ratio plays an important role in diabetic cognitive dysfunction, and rIL-22 can effectively alleviate DE. Herein, we shed light on the interaction between IL-22 and IL-22BP as therapeutic targets for DM.

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Acknowledgements

This project was supported by grants from China Postdoctoral Science Foundation (No. 2017M612870) and Natural Science Foundation of Liaoning Province (No. 2019-ZD-0807).

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Author notes

  1. Xiaobai Wang and Shengxue Yu have contributed equally to this work and share first authorship.

  2. Wenqiang Liu, Pan Lv, Lipan Zhao, Yufei Wang, Cong Fu, Lu Meng, Qi Yang, Xuehua Wang, Ying Huang, these authors have contributed equally to this work.

Authors and Affiliations

  1. Liaoning Key Laboratory of Diabetic Cognitive and Perceptive Dysfunction, Jinzhou Medical University, Jinzhou, China

    Xiaobai Wang, Shengxue Yu, Wenqiang Liu, Pan Lv, Lipan Zhao, Yufei Wang, Cong Fu, Lu Meng, Qi Yang, Xuehua Wang, Ying Huang, Zhongfu Zuo & Xuezheng Liu

  2. Department of Anatomy, Histology and Embryology, Jinzhou Medical University, Jinzhou, China

    Xiaobai Wang, Shengxue Yu, Wenqiang Liu, Pan Lv, Lipan Zhao, Yufei Wang, Cong Fu, Lu Meng, Qi Yang, Xuehua Wang, Ying Huang, Zhongfu Zuo & Xuezheng Liu

  3. Department of Anatomy, Histology and Embryology, Postdoctoral Research Station, Guangxi Medical University, Nanning, China

    Zhongfu Zuo

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Contributions

XB-W and SX-Y contributed to experiments, data collection, manuscript writing. WQ-L, LP, LP-Z, YF-W, CF, and LM provide help for experimental testing and theoretical support. QY, XH-W, and YH help collect experimental data. XZ-L and ZF-Z contributed to experimental conception, data interpretation and manuscript revision. All authors have read and approved the submission and publication of the final version of manuscript. The authors vouch for the accuracy and completeness of the experiment.

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Correspondence to Zhongfu Zuo or Xuezheng Liu.

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Reports of animal experiments state that the “Principles of laboratory animal care” (NIH publication No. 86-23, revised 1985) were followed, and was reviewed and approved by the Laboratory Animal Ethics Committee of Jinzhou Medical University.

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Wang, X., Yu, S., Liu, W. et al. Relationship between IL-22 and IL-22BP in diabetic cognitive dysfunction. Acta Diabetol 60, 631–644 (2023). https://doi.org/10.1007/s00592-022-02024-5

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