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Th22 cells induce Müller cell activation via the Act1/TRAF6 pathway in diabetic retinopathy

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Abstract

T helper 22 (Th22) cells have been implicated in diabetic retinopathy (DR), but it remains unclear whether Th22 cells involve in the pathogenesis of DR. To investigate the role of Th22 cells in DR mice, the animal models were established by intraperitoneal injection of STZ and confirmed by fundus fluorescein angiography and retinal haematoxylin–eosin staining. IL-22BP was administered by intravitreal injection. IL-22 level was measured by ELISA in vivo and in vitro. The expression of IL-22Rα1 in the retina was assessed by immunofluorescence. We assessed GFAP, VEGF, ICAM-1, inflammatory-associated factors and the integrity of blood–retinal barrier in control, DR, IL-22BP, and sham group. Müller cells were co-cultured with Th22 cells, and the expression of the above proteins was measured by immunoblotting. Plasmid transfection technique was used to silence Act1 gene in Müller cells. Results in vivo and in vitro indicated that Th22 cells infiltrated into the DR retinal and IL-22Rα1 expressed in Müller cells. Th22 cells promoted Müller cells activation and inflammatory factor secretion by secreting IL-22 compared with high-glucose stimulation alone. In addition, IL-22BP ameliorated the pathological alterations of the retina in DR. Inhibition of the inflammatory signalling cascade through Act1 knockdown alleviated DR-like pathology. All in all, the results suggested that Th22 cells infiltrated into the retina and secreted IL-22 in DR, and then IL-22 binding with IL-22Rα1 activated the Act1/TRAF6 signal pathway, and promoted the inflammatory of Müller cells and involved the pathogenesis of DR.

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All relevant data generated or analyzed during this study are included in this published article.

Abbreviations

DR:

Diabetic retinopathy

BRB:

Blood–retinal barrier

iBRB:

Inner blood–retinal barrier

oBRB:

Outer blood–retinal barrier

STZ:

Streptozotocin

FFA:

Fundus fluorescein angiography;

HE:

Haematoxylin-eosin staining;

GFAP:

Glial fibrillary acidic protein

VEGF:

Vascular endothelial growth factor;

ICAM-1:

Intercellular adhesion molecule-1

GS:

Glutamate synthase

IL-22BP:

IL-22 binding protein

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Funding

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

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Author notes

  1. Yufei Wang and Hongdan Yu contributed equally to this work and share first authorship.

  2. Jing Li, Wenqiang Liu, Shengxue Yu, Pan Lv, Lipan Zhao, and Xiaobai Wang contributed equally to this work.

Authors and Affiliations

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

    Yufei Wang, Hongdan Yu, Jing Li, Wenqiang Liu, Shengxue Yu, Pan Lv, Lipan Zhao, Xiaobai Wang, Zhongfu Zuo & Xuezheng Liu

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

    Yufei Wang, Hongdan Yu, Wenqiang Liu, Shengxue Yu, Pan Lv, Lipan Zhao, Xiaobai Wang, 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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  1. Yufei Wang
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Contributions

YFW and HDY contributed to experiments, data collection, manuscript writing. JL, WQL and SXY provide help for experimental testing and theoretical support. LPZ, LP and XBW help collect experimental data. XZL and ZFZ 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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Ethics approval for all animal experiments was obtained from the institutional animal care and use Committee of Jinzhou Medical University [SYXK• [ Liao] •2019–0007].

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Wang, Y., Yu, H., Li, J. et al. Th22 cells induce Müller cell activation via the Act1/TRAF6 pathway in diabetic retinopathy. Cell Tissue Res 390, 367–383 (2022). https://doi.org/10.1007/s00441-022-03689-8

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