RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation

J Allergy Clin Immunol. 2016 Jan;137(1):231-245.e4. doi: 10.1016/j.jaci.2015.05.004. Epub 2015 Jun 19.

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.

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

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology
  • Animals
  • Cell Differentiation
  • Glycolysis*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Mice, Knockout
  • Mice, Transgenic
  • Ovalbumin / immunology
  • Respiratory Hypersensitivity / immunology
  • Respiratory Hypersensitivity / metabolism*
  • Th2 Cells / cytology
  • Th2 Cells / immunology
  • Th2 Cells / metabolism*
  • rhoA GTP-Binding Protein / deficiency
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / immunology
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Allergens
  • Ovalbumin
  • rhoA GTP-Binding Protein