RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:137

Article

Yang, Jun-Qi^1,2  Kalim, Khalid W.¹  Li, Yuan¹  Zhang, Shuangmin¹  Hinge, Ashwini¹  Filippi, Marie-Dominique¹  Zheng, Yi¹  Guo, Fukun¹ 

[1] Childrens Hosp Res Fdn, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[2] Jiangsu Inst Parasit Dis, Key Lab Parasit Dis Control & Prevent, Minist Hlth, Wuxi, Peoples R China

关键词: RhoA;    T-cell metabolism;    glycolysis;    T(H)2 differentiation;    allergic airway inflammation;   

DOI  :  10.1016/j.jaci.2015.05.004

来源: Elsevier

【 摘 要 】

Background: Mitochondrial metabolism is known to be important for T-cell activation. However, its involvement in effector T-cell differentiation has just begun to gain attention. Importantly, how metabolic pathways are integrated with T-cell activation and effector cell differentiation and function remains largely unknown. Objective: We sought to test our hypothesis that RhoA GTPase orchestrates glycolysis for T(H)2 cell differentiation and T(H)2-mediated allergic airway inflammation. Methods: Conditional RhoA-deficient mice were generated by crossing RhoA(flox/flox) mice with CD2-Cre transgenic mice. Effects of RhoA on T(H)2 differentiation were evaluated based on in vitro T(H)2-polarized culture conditions and in vivo in ovalbumin-induced allergic airway inflammation. Cytokine levels were measured by using intracellular staining and ELISA. T-cell metabolism was measured by using the Seahorse XF24 Analyzer and flow cytometry. Results: Disruption of RhoA inhibited T-cell activation and T(H)2 differentiation in vitro and prevented the development of allergic airway inflammation in vivo, with no effect on T(H)1 cells. RhoA deficiency in activated T cells led to multiple defects in metabolic pathways, such as glycolysis and oxidative phosphorylation. Importantly, RhoA couples glycolysis to T(H)2 cell differentiation and allergic airway inflammation through regulating IL-4 receptor mRNA expression and T(H)2-specific signaling events. Finally, inhibition of Rho-associated protein kinase, an immediate downstream effector of RhoA, blocked T(H)2 differentiation and allergic airway inflammation. Conclusion: RhoA is a key component of the signaling cascades leading to T(H)2 differentiation and allergic airway inflammation at least in part through control of T-cell metabolism and the Rho-associated protein kinase pathway.

【 授权许可】

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