Integrated single-cell transcriptomic and chromatin-accessibility analyses reveal convergent immune regulation linking inflammation to airway remodeling in chronic asthma

Persistent airway inflammation and structural remodeling jointly contribute to lung function decline and incomplete treatment response in chronic asthma. Although heterogeneous immune and stromal states have been described, whether distinct inflammatory populations converge on shared regulatory programs remains unclear. We aimed to characterize this regulatory convergence, examine its association with inflammation and remodeling, and assess its clinical relevance in asthma. We integrated single-cell RNA sequencing and chromatin-accessibility profiling generated from lung tissues of the same 16-week house dust mite-induced chronic asthma mouse cohort. Cross-modal analyses included matched cell-state annotation, chromatin accessibility and transcription-factor inference, and cell-cell communication analysis. Key regulatory findings were examined experimentally and evaluated in independent human sputum transcriptomic cohorts. Macrophage subsets and IL-17 A-producing γδT17 cells showed convergent NF-κB-HIF1A-AP-1-associated regulatory features, with macrophages exhibiting inflammatory and remodeling-associated states and γδT17 cells showing heightened inflammatory activation. In parallel, fibroblasts displayed MEOX2-associated inflammatory and MEF2C-associated contractile remodeling states. Functional perturbation supported the involvement of MEOX2 and MEF2C in inflammatory and remodeling-associated transcriptional programs, respectively. Cell-cell communication analyses predicted coordinated TNF, IL-1, IL-17, CXCL12, and POSTN signaling, delineating a putative γδT17-macrophage-fibroblast network linking persistent inflammation to airway remodeling. Supporting the clinical relevance of the regulatory convergence, an NF-κB-HIF1A-AP-1 regulatory score showed greater discrimination of severe asthma than selected downstream effector signatures and was associated with corticosteroid use, granulocytic inflammation, and impaired lung function in independent sputum cohorts. These findings define a cross-lineage regulatory framework in which convergent immune regulation in macrophages and γδT17 cells is associated with distinct fibroblast remodeling states and predicted intercellular signaling. This framework provides a potential regulatory link between persistent inflammation and airway remodeling and identifies a shared regulatory signature with potential relevance to molecular stratification in severe asthma.