A model of human asthma exacerbation identifies novel transcriptional programs and pathogenic cell circuits in the lower airway mucosa specific to allergic asthma

Using a human model of asthma exacerbation, we compared the airway mucosa in allergic asthmatics and allergic non-asthmatic controls using single-cell RNA-sequencing frameworks. In response to allergen challenge, the airway epithelium in asthmatics was highly dynamic and upregulated genes involved in matrix degradation, mucus metaplasia, and glycolysis while failing to induce injury-repair and antioxidant pathways observed in controls. Asthmatics also had a unique mucosal immune profile, characterized by IL9-expressing pathogenic TH2 cells and enrichment of DC2 (CD1C) and CCR2-expressing monocyte-derived cells (MC) after allergen, with upregulation of genes that promote pathologic airway remodeling. In contrast, controls were enriched for macrophage-like MC that upregulated tissue repair programs after allergen challenge, suggesting these populations may protect against asthmatic airway remodeling. These findings reveal a novel TH2-mononuclear phagocyte-epithelial interactome unique to asthmatics, suggesting that pathogenic effector circuits and the absence of pro-resolution programs drive structural airway disease in response to type 2 inflammation.