Division of Experimental Hematology and Cancer Biology, Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Key Laboratory of National Health Commission on Parasitic Disease Control and Prevention, Jiangsu Provincial Key Laboratory on Parasitic and Vector Control, Jiangsu Institute of Parasitic Diseases and Public Health Research Center, Jiangnan University, Wuxi, Jiangsu, China.
J Leukoc Biol. 2019 Nov;106(5):1139-1151. doi: 10.1002/JLB.3A0119-025RRR. Epub 2019 Jul 1.
Asthma is a heterogeneous chronic airway inflammation in which Th2 and Th17 cells are key players in its pathogenesis. We have reported that RhoA of Rho GTPases orchestrated glycolysis for Th2 cell differentiation and allergic airway inflammation by the use of a conditional RhoA-deficient mouse line. However, the role of RhoA in Th17 cells remains to be elucidated. In this study, we investigated the effects of RhoA deficiency on Th17 cells in the context of ex vivo cell culture systems and an in vivo house dust mites (HDM)-induced allergic airway inflammation. We found that RhoA deficiency inhibited Th17 differentiation and effector cytokine secretion, which was associated with the downregulations of Stat3 and Rorγt, key Th17 transcription factors. Furthermore, loss of RhoA markedly suppressed Th17 and neutrophil-involved airway inflammation induced by HDM in mice. The infiltrating inflammatory cells in the lungs and bronchoalveolar lavage (BAL) fluids were dramatically reduced in conditional RhoA-deficient mice. Th17 as well as Th2 effector cytokines were suppressed in the airways at both protein and mRNA levels. Interestingly, Y16, a specific RhoA inhibitor, was able to recapitulate the most phenotypes of RhoA genetic deletion in Th17 differentiation and allergic airway inflammation. Our data demonstrate that RhoA is a key regulator of Th17 cell differentiation and function. RhoA might serve as a potential novel therapeutic target for asthma and other inflammatory disorders.
哮喘是一种异质性的慢性气道炎症，其中 Th2 和 Th17 细胞是其发病机制中的关键因素。我们曾报道过，RhoA 作为 Rho GTPases 的一种，可以通过使用条件性 RhoA 缺陷小鼠系来协调糖酵解，从而促进 Th2 细胞分化和过敏性气道炎症。然而，RhoA 在 Th17 细胞中的作用仍有待阐明。在本研究中，我们在体外细胞培养系统和体内屋尘螨（HDM）诱导的过敏性气道炎症中研究了 RhoA 缺陷对 Th17 细胞的影响。我们发现，RhoA 缺陷抑制了 Th17 细胞的分化和效应细胞因子的分泌，这与关键的 Th17 转录因子 Stat3 和 Rorγt 的下调有关。此外，RhoA 的缺失显著抑制了由 HDM 诱导的小鼠 Th17 和中性粒细胞参与的气道炎症。在条件性 RhoA 缺陷小鼠中，肺部和支气管肺泡灌洗液（BAL）中的浸润性炎症细胞显著减少。气道中的 Th17 以及 Th2 效应细胞因子在蛋白和 mRNA 水平上均受到抑制。有趣的是，Y16，一种特异性的 RhoA 抑制剂，能够在 Th17 分化和过敏性气道炎症中再现 RhoA 基因缺失的大多数表型。我们的数据表明，RhoA 是 Th17 细胞分化和功能的关键调节因子。RhoA 可能成为哮喘和其他炎症性疾病的潜在新型治疗靶点。
