RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation.
J Allergy Clin Immunol
; 137(1): 231-245.e4, 2016 Jan.
Article
em En
| MEDLINE
| ID: mdl-26100081
ABSTRACT
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 TH2 cell differentiation and TH2-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 TH2 differentiation were evaluated based on in vitro TH2-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 TH2 differentiation in vitro and prevented the development of allergic airway inflammation in vivo, with no effect on TH1 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 TH2 cell differentiation and allergic airway inflammation through regulating IL-4 receptor mRNA expression and TH2-specific signaling events. Finally, inhibition of Rho-associated protein kinase, an immediate downstream effector of RhoA, blocked TH2 differentiation and allergic airway inflammation.CONCLUSION:
RhoA is a key component of the signaling cascades leading to TH2 differentiation and allergic airway inflammation at least in part through control of T-cell metabolism and the Rho-associated protein kinase pathway.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Hipersensibilidade Respiratória
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Células Th2
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Proteína rhoA de Ligação ao GTP
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Glicólise
Limite:
Animals
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article