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.

中文翻译：

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HDAC6特异性抑制剂在小鼠急性肺移植排斥反应中通过HIF-1α途径抑制Th17细胞功能。

背景：先前的动物实验和临床研究表明Th17细胞在肺移植排斥反应中的关键作用。因此，肺移植受者中Th17细胞功能的下调引起了极大的兴趣。方法：我们建立了原位小鼠肺移植模型，以研究组蛋白脱乙酰基酶6特异性抑制剂（HDAC6i）Tubastatin A在抑制同种异体移植物中Th17细胞和减轻病理损伤中的作用。此外，在体外进行了机理研究。结果：Tubastatin A下调急性同种异体移植排斥反应中Th17细胞的功能，延长肺同种异体移植物的存活时间，并通过抑制Th17细胞积累来减轻急性排斥反应。一致地，外源性IL-17A补充消除了Tubastatin A的保护作用。此外，在肺移植小鼠模型中过氧诱导因子1α（HIF-1α）过表达。HIF-1α缺乏通过下调视黄酸相关的孤儿受体γt（RORγt）的表达来抑制Th17细胞功能并减弱肺移植排斥反应。我们表明，HDAC6i在Th17偏斜条件下在体外下调了HIF-1α转录活性，并促进了同种异体移植肺中HIF-1α蛋白的降解。HDAC6i不影响对HIF-1α ^-/-幼稚CD4的抑制⁺ T细胞分化为Th17细胞并减轻了HIF-1α缺陷受体小鼠的急性肺移植排斥反应。结论：这些发现表明，Tubastatin A通过HIF-1α/RORγt途径至少部分下调了Th17细胞功能并抑制了急性肺移植排斥反应。