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Th17/IL-17 induces endothelial cell senescence via activation of NF-κB/p53/Rb signaling pathway

Abstract

Cellular senescence is a key mechanism of age-related vascular endothelial dysfunction. Interleukin-17A (IL-17A) is an inflammatory cytokine produced by Th17 cells (a subgroup of helper T cells), which is a key factor in the development of atherosclerosis. However, the effect of IL-17A on the senescence of vascular endothelial cells is still unclear. In this study, we aimed to explore the role of IL-17A on endothelial cell senescence and its signaling pathways associated with senescence. The proportion of Th17 cells in the spleen and the expression levels of IL-17A, IL-6, and vascular cell adhesion molecule-1 (VCAM-1) in mice of different ages were increased with aging. In vitro experiments showed that proliferation was inhibited, senescent β-galactosidase and senescence-associated proteins (p16, p19, p21, and p53) of mouse aortic endothelial cells (MAECs) were increased with IL-17A treatment. Blocking the NF-κB pathway with ammonium pyrrolidinedithiocarbamate (PDTC) successfully inhibited IL-17A-induced expression of senescence-associated proteins. In conclusion, our data reveal a previously unsuspected link between IL-17A and endothelial cell senescence, which was mediated by the NF-κB /p53/Rb pathway.

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Fig. 1: The morphology of mouse arteries and the expression of Th17 cells and IL-17A, IL-6, VCAM-1 of different age mice.
Fig. 2: Immunological identification, senescence staining and SAHF observation of the primary endothelial cells from each group.
Fig. 3: Effects of different concentrations of IL-17A on senescence of mouse aortic endothelial cells.
Fig. 4: Flow cytometry and immunohistochemistry were used to detect the expression levels of the IL-17A/IL-17 receptor A (IL-17RA) and to assess the endothelial cell cycle.
Fig. 5: The expression levels of NF-κB, its phosphorylated proteins and those of the p53/Rb senescence pathway proteins were detected by western blot analysis.

Data availability

The datasets used during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This study was supported by the International Cooperative Project of Anhui Province of China (No. 201904b11020045), Province science and technology in the Anhui offends pass item (No.201904a07020086), and the Fundamental Research Funds for the Central Universities (Nos. WK9110000149, WK9110000084, WK9110000012).

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L.Z., W.H., and Y.P.W. designed and supervised the study; L.Z., M.L.L., C.J.H., and W.H.L. performed animal experiments and in vitro experiments, and analyzed data; Q.L., W.H.L., and H.Q.L. assisted in flow cytometry and provided reagents and expertise; Q.L., Y.P.W., Q.C., J.D., and W.H. participated in discussions, provided intellectual input; L.Z. and M.L.L and wrote the paper. All authors have read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Wei Hu or Qing Li.

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Zhang, L., Liu, M., Liu, W. et al. Th17/IL-17 induces endothelial cell senescence via activation of NF-κB/p53/Rb signaling pathway. Lab Invest 101, 1418–1426 (2021). https://doi.org/10.1038/s41374-021-00629-y

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