Blockade of dendritic cell glutaminolysis induces allergic asthma desensitization via suppression of Tfh13 polarization

Abstract

Allergic asthma is a pulmonary disease characterized by airway hyperresponsiveness (AhR) in response to inhaled allergens. AhR is largely mediated by allergen-specific (Ag-specific) IgE induced mast cell (MC) degranulation which drives inflammation of the airways following allergen exposure. Ag-specific IgE production requires T follicular helper 13 cells (Tfh13s) which must first be polarized by dendritic cells (DCs). The mechanisms by which DCs polarize Tfh13s, however, are unclear. We hypothesized that the Tfh13 inducing allergen Alternaria would induce a unique metabolic response compared to non-Tfh13 inducing stimuli. We found, by untargeted metabolomic analysis, that Alternaria induced accumulation of the glutamine-derived TCA cycle metabolite α-ketoglutarate compared to LPS stimulated or unstimulated DCs. Glutamine is converted to α-ketoglutarate by glutaminase (Gls), so we predicted that inhibition of Gls may suppress Tfh13 polarization by DCs. Indeed, we found that treatment with the Gls inhibitor, CB-839, reduced Tfh13 polarization and increased T follicular regulatory cells following Alternaria exposure. This finding was recapitulated in a DC adoptive transfer model, indicating that this mechanism is DC intrinsic. We next tested if CB-839 causes allergen desensitization in a model of allergic asthma. Mice were intranasally sensitized and challenged with Alternaria and intranasally treated with CB-839 or vehicle control prior to challenge. CB-839 treated mice exhibited reduced AhR, Ag-specific IgE, and airway MC degranulation. These data demonstrate that DC glutaminolysis is required for Tfh13 polarization, and that Gls inhibitors may promote allergen desensitization in allergic asthma. This work was funded by VCU's National Center for Advancing Translational Sciences (UL1TR002649) and NIAID (R56AI139658).