We leveraged a translational model of asthma exacerbation in allergic asthmatics (AA) and allergic non-asthmatic controls (AC) to identify tissue-specific pathways driving asthma pathogenesis.
We performed single-cell RNA-sequencing of airway mucosal cells collected in vivo at homeostasis and after segmental allergen challenge (SAC). Logistic regression and LASSO modeling identified cellular and transcriptional programs associated with each group. CellphoneDB predicted receptor-ligand interactions specific to each group. Bronchoalveolar lavage (BAL) protein levels were quantified via multiplex assay.
Type-2 T helper cells (TH2) (OR 3.43, [1.87-6.29]), inflammatory type 2 dendritic cells (DC2) (OR 2.11, [1.23-3.61]) and CCR2hi monocyte-derived cells (MC) (OR 2.77, [1.29-5.92]) were enriched in AA after SAC, while macrophage-like MC that maintain airway homeostasis were enriched in AC. Lymphotoxin (LT) genes positively associated with DC2 enrichment in AA and negatively associated with macrophage-like MC in AC (P<0.01).LT-a levels increased after SAC in AA but not AC (147.3 vs. 18.2 pg/mL, P=0.04). TH2-DC2 interactions promoting DC maturation (e.g., LT signaling) and TH2 chemotaxis and polarization were asthma-specific (P<0.001).
We identified novel airway immune circuits that distinguish asthma from allergy. A feedforward circuit of DC maturation and TH2 activation via LT signaling may provide a novel target for disease remission in asthma.