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

Abstract

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.

Immune Metabolism in TH2 Responses: New Opportunities to Improve Allergy Treatment — Cell Type-Specific Findings (Part 2)

“…As first shown by Tibbitt et al [ 28 ] and later confirmed by Healey et al [ 29 ], metabolically, in vitro-differentiated Th2 cells were shown to display the highest levels of glycolysis of all T helper cell subsets while also having a high mitochondrial oxygen consumption. Furthermore, Th2 cytokine secretion was shown to be glycolysis-dependent, while ex vivo -isolated BALF Th2 cells from a HDM-mouse model showed no enrichment of genes related to glycolysis [ 28 ].…”

“…Activated T cells increase their uptake of glutamine and lack of glutamine was shown to impair both their cytokine secretion and proliferation [ 27 ]. In 2021, Healey et al analyzed the bronchoalveolar lavage fluid (BALF) of asthmatic patients and found hints of a generally enhanced metabolism (as shown by higher lactate concentrations after allergen challenge) and markers for both increased glycolysis and glutamine metabolism [ 29 ]. In mice sensitized to Alternaria alternate extract, enhanced OxPhos, glucose, and glutamine metabolism were observed in both Th2 and Th17 cells, while Th17 cells also had a higher potential for glutamine metabolism [ 29 ].…”

Regulation of immune cell metabolism in health and disease: Special focus on T and B cell subsets

“…It has been reported that GLS‐1 mediated glutaminolysis contributes to psoriasis pathogenesis through the induction of Th17 and γδ Th17 cell differentiation, but not Th1 cell or iTreg differentiation (Xia et al, 2020). Effectors Th2 and Th17 cells promote inflammation in asthmatic patients and analysis of bronchoalveolar lavage fluid of asthmatic patients had shown elevated markers of glucose and glutamine metabolism which supports Th1 and Th17 cell differentiation (Healey et al, 2021). As we know Th17 cells rely on de‐novo synthesis of fatty acids, it was demonstrated that mice fed with high trans fatty acids exhibited higher Th17 cells and ROR‐γt expression with increased Th17 response which develops colitis and other inflammation in response to dextran sodium sulfate (Berod et al, 2014; Okada et al, 2013).…”

Neuronal-Immune Cell Units in Allergic Inflammation in the Nose

“…Eosinophil-derived major basic protein operates as an antagonist of M2AchR, inhibiting the negative feedback loop and potentiating oversecretion of ACh that leads to bronchoconstriction in the lungs [22]. L-Glu has been reported to increase in eosinophils upon hyper-responsiveness of the unified airway [41]. Histamine [42] and NMU [59] stimulate eosinophil migration, NGF promotes the activation and degranulation of eosinophils [18], whereas adenosine inhibits their accumulation at the inflammatory sites [89].…”