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Theranostics 2020; 10(15):6790-6805. doi:10.7150/thno.44961 This issue Cite

Research Paper

HDAC6-specific inhibitor suppresses Th17 cell function via the HIF-1α pathway in acute lung allograft rejection in mice

Wenyong Zhou1✉*, Jun Yang1*, Gaowa Saren2*, Heng Zhao1, Kejian Cao1, Shijie Fu1, Xufeng Pan1, Huijun Zhang3, An Wang3, Xiaofeng Chen3✉

1. Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
2. Department of Intensive Care, Huashan Hospital, Fudan University, Shanghai, China.
3. Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China.
*These authors contributed equally to this work.

✉ Corresponding authors: Wenyong Zhou (123zwyedu.cn); Xiaofeng Chen (dr_xiaofeng_chencom)

Citation:
Zhou W, Yang J, Saren G, Zhao H, Cao K, Fu S, Pan X, Zhang H, Wang A, Chen X. HDAC6-specific inhibitor suppresses Th17 cell function via the HIF-1α pathway in acute lung allograft rejection in mice. Theranostics 2020; 10(15):6790-6805. doi:10.7150/thno.44961. https://www.thno.org/v10p6790.htm
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Abstract

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Background: Previous animal experiments and clinical studies indicated the critical role of Th17 cells in lung transplant rejection. Therefore, the downregulation of Th17 cell function in lung transplant recipients is of great interest. Methods: We established an orthotopic mouse lung transplantation model to investigate the role of histone deacetylase 6-specific inhibitor (HDAC6i), Tubastatin A, in the suppression of Th17 cells and attenuation of pathologic lesions in lung allografts. Moreover, mechanism studies were conducted in vitro. Results: Tubastatin A downregulated Th17 cell function in acute lung allograft rejection, prolonged the survival of lung allografts, and attenuated acute rejection by suppressing Th17 cell accumulation. Consistently, exogenous IL-17A supplementation eliminated the protective effect of Tubastatin A. Also, hypoxia-inducible factor-1α (HIF-1α) was overexpressed in a lung transplantation mouse model. HIF-1α deficiency suppressed Th17 cell function and attenuated lung allograft rejection by downregulating retinoic acid-related orphan receptor γt (ROR γt) expression. We showed that HDAC6i downregulated HIF-1α transcriptional activity under Th17-skewing conditions in vitro and promoted HIF-1α protein degradation in lung allografts. HDAC6i did not affect the suppression of HIF-1α-/- naïve CD4+ T cell differentiation into Th17 cell and attenuation of acute lung allograft rejection in HIF-1α-deficient recipient mice. Conclusion: These findings suggest that Tubastatin A downregulates Th17 cell function and suppresses acute lung allograft rejection, at least partially, via the HIF-1α/ RORγt pathway.

Keywords: lung transplantation, acute rejection, mouse, HIF-1α, Th17 cells, HDAC6i

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APA
Zhou, W., Yang, J., Saren, G., Zhao, H., Cao, K., Fu, S., Pan, X., Zhang, H., Wang, A., Chen, X. (2020). HDAC6-specific inhibitor suppresses Th17 cell function via the HIF-1α pathway in acute lung allograft rejection in mice. Theranostics, 10(15), 6790-6805. https://doi.org/10.7150/thno.44961.

ACS
Zhou, W.; Yang, J.; Saren, G.; Zhao, H.; Cao, K.; Fu, S.; Pan, X.; Zhang, H.; Wang, A.; Chen, X. HDAC6-specific inhibitor suppresses Th17 cell function via the HIF-1α pathway in acute lung allograft rejection in mice. Theranostics 2020, 10 (15), 6790-6805. DOI: 10.7150/thno.44961.

NLM
Zhou W, Yang J, Saren G, Zhao H, Cao K, Fu S, Pan X, Zhang H, Wang A, Chen X. HDAC6-specific inhibitor suppresses Th17 cell function via the HIF-1α pathway in acute lung allograft rejection in mice. Theranostics 2020; 10(15):6790-6805. doi:10.7150/thno.44961. https://www.thno.org/v10p6790.htm

CSE
Zhou W, Yang J, Saren G, Zhao H, Cao K, Fu S, Pan X, Zhang H, Wang A, Chen X. 2020. HDAC6-specific inhibitor suppresses Th17 cell function via the HIF-1α pathway in acute lung allograft rejection in mice. Theranostics. 10(15):6790-6805.

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