D-2-hydroxyglutarate decreases allergic sensitization in asthma

Abstract Allergic asthma is a chronic inflammatory disease affecting the lungs which is mediated by allergen-specific IgE and type 2 cytokines. IgE and type 2 cytokine production require Tfh13 cell and Th2 cell polarization, respectively, which must first be primed by dendritic cells (DC). Recent studies demonstrate that cellular metabolic perturbations critically regulate DC activation and subsequent T cell priming. To characterize DC metabolic mechanisms which may regulate allergic sensitization, we analyzed GWAS data to identify metabolism-related genes that are associated with asthma risk. We identified 384 single nucleotide polymorphisms (SNPs) in the D2HGDHlocus that are significantly associated with childhood-onset asthma. Further, expression quantitative trait loci analysis of the 10 most significant SNPs revealed that these SNPs promote reduced expression of D2HGDHmRNA. D2HGDH is an enzyme which catalyzes the conversion of D-2-hydroxyglutarate (D-2HG) to α-ketoglutarate (aKG). D-2HG is a potent inhibitor of aKG-dependent epigenetic enzymes. Bone marrow-derived dendritic cells (BMDCs) stimulated with the fungal allergen Alternariaexhibited a significant increase in the ratio of aKG/D-2HG compared to mock or LPS treated BMDCs. Further, in vivostudies revealed that intranasal administration of cell-permeable D-2HG prior to intranasal exposure to Alternariasignificantly reduced Th2 and Tfh13 polarization, impaired IgE+ germinal center B cell differentiation, and induced T follicular regulatory cell polarization in mice. Our results suggest a mechanism whereby D-2HG suppresses epigenetic modifications in DCs, which are necessary for allergic sensitization and polarization of Th2 and Tfh13 cells. VCU CTSA UL1TR002649 as well as funding from NIAID R56AI139658