Targeting In Vivo Metabolic Vulnerabilities of Th2 and Th17 Cells Reduces Airway Inflammation.

Journal Article (Journal Article)

T effector cells promote inflammation in asthmatic patients, and both Th2 and Th17 CD4 T cells have been implicated in severe forms of the disease. The metabolic phenotypes and dependencies of these cells, however, remain poorly understood in the regulation of airway inflammation. In this study, we show the bronchoalveolar lavage fluid of asthmatic patients had markers of elevated glucose and glutamine metabolism. Further, peripheral blood T cells of asthmatics had broadly elevated expression of metabolic proteins when analyzed by mass cytometry compared with healthy controls. Therefore, we hypothesized that glucose and glutamine metabolism promote allergic airway inflammation. We tested this hypothesis in two murine models of airway inflammation. T cells from lungs of mice sensitized with Alternaria alternata extract displayed genetic signatures for elevated oxidative and glucose metabolism by single-cell RNA sequencing. This result was most pronounced when protein levels were measured in IL-17-producing cells and was recapitulated when airway inflammation was induced with house dust mite plus LPS, a model that led to abundant IL-4- and IL-17-producing T cells. Importantly, inhibitors of the glucose transporter 1 or glutaminase in vivo attenuated house dust mite + LPS eosinophilia, T cell cytokine production, and airway hyperresponsiveness as well as augmented the immunosuppressive properties of dexamethasone. These data show that T cells induce markers to support metabolism in vivo in airway inflammation and that this correlates with inflammatory cytokine production. Targeting metabolic pathways may provide a new direction to protect from disease and enhance the effectiveness of steroid therapy.

Full Text

Duke Authors

Cited Authors

  • Healey, DCC; Cephus, JY; Barone, SM; Chowdhury, NU; Dahunsi, DO; Madden, MZ; Ye, X; Yu, X; Olszewski, K; Young, K; Gerriets, VA; Siska, PJ; Dworski, R; Hemler, J; Locasale, JW; Poyurovsky, MV; Peebles, RS; Irish, JM; Newcomb, DC; Rathmell, JC

Published Date

  • March 15, 2021

Published In

Volume / Issue

  • 206 / 6

Start / End Page

  • 1127 - 1139

PubMed ID

  • 33558372

Pubmed Central ID

  • PMC7946768

Electronic International Standard Serial Number (EISSN)

  • 1550-6606

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.2001029

Language

  • eng

Conference Location

  • United States