RhoA orchestrates glycolysis for T_H2 cell differentiation and allergic airway inflammation

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• 作者：Jun-Qi Yang ; PhD^a ; ^b ; Khalid W. Kalim ; PhD^a ; Yuan Li ; MS^a ; Shuangmin Zhang ; PhD^a ; Ashwini Hinge ; PhD^a ; Marie-Dominique Filippi ; PhD^a ; Yi Zheng ; PhD^a ; Fukun Guo ; PhD^a ; ^{fukun.guo@cchmc.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：RhoA ; T-cell metabolism ; glycolysis ; TH2 differentiation ; allergic airway inflammation
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：137
• 期：1
• 页码：231-245.e4
• 全文大小：5038 K

文摘

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_H2 cell differentiation and T_H2-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_H2 differentiation were evaluated based on in vitro T_H2-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_H2 differentiation in vitro and prevented the development of allergic airway inflammation in vivo, with no effect on T_H1 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_H2 cell differentiation and allergic airway inflammation through regulating IL-4 receptor mRNA expression and T_H2-specific signaling events. Finally, inhibition of Rho-associated protein kinase, an immediate downstream effector of RhoA, blocked T_H2 differentiation and allergic airway inflammation.

Conclusion

RhoA is a key component of the signaling cascades leading to T_H2 differentiation and allergic airway inflammation at least in part through control of T-cell metabolism and the Rho-associated protein kinase pathway.