title: RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio; Key Laboratory for Parasitic Disease Control and Prevention, Ministry of Health, Jiangsu Institute of Parasitic Diseases, Wuxi, China.
authors.forename: Jun-Qi
authors.initials: JQ
authors.lastname: Yang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.
authors.forename: Khalid W
authors.initials: KW
authors.lastname: Kalim
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.
authors.forename: Shuangmin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Hinge
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.
authors.forename: Marie-Dominique
authors.initials: MD
authors.lastname: Filippi
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio. Electronic address: fukun.guo@cchmc.org.
authors.forename: Fukun
authors.initials: F
authors.lastname: Guo
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D002454:Cell Differentiation; D006019:Glycolysis; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000485:Allergens; D010047:Ovalbumin; D020742:rhoA GTP-Binding Protein
keywords: RhoA; T(H)2 differentiation; T-cell metabolism; allergic airway inflammation; glycolysis