BACKGROUND

Asthma is a chronic inflammatory airway disease characterized by recurrent episodes that significantly impair disease control and reduce patients' quality of life. Despite its clinical importance, the mechanisms underlying asthma relapse remain poorly understood, and effective strategies to prevent exacerbations are still lacking.

METHODS

An acute allergic asthma relapse mouse model was established using ovalbumin sensitization and challenge. Single-cell transcriptomics was employed to investigate the cellular and molecular mechanisms driving asthma relapse. Flow cytometry and gene knockout experiments were conducted to validate the findings.

RESULTS

We successfully established an acute allergic asthma relapse mouse model. Single-cell transcriptomic analysis revealed that T cells and type 2 innate lymphoid cells (ILC2s) are pivotal during asthma relapse, serving as the primary cellular sources of type 2 inflammatory cytokines. Further subcluster analysis identified T-cell subcluster 4 and ILC2 subcluster 0 as the predominant contributors to type 2 cytokine production. Complex intercellular communication networks were observed, with macrophages, natural killer (NK) cells, and dendritic cells functioning as central signaling hubs. Pseudo-time trajectory analysis highlighted the critical role of ILC2s and the Il1rl1 signaling pathway in asthma relapse. These findings were corroborated by flow cytometry. Il1rl1-deficient mice displayed similar pulmonary inflammation to wild-type mice during the initial asthma episode; however, asthma relapse was significantly attenuated. Mechanistically, Il1rl1 deficiency resulted in a substantial reduction in both the number and functional capacity of ILC2s.

CONCLUSION

The recurrence of acute allergic asthma is driven, at least in part, by ILC2s through Il1rl1 signaling. Genetic ablation of Il1rl1 significantly suppresses asthma relapse, suggesting that targeting Il1rl1 may represent a novel therapeutic strategy for preventing asthma exacerbations.