Pharmacological AhR activation attenuates airway hyperresponsiveness and remodeling in a mixed allergen asthma model

Airway hyperresponsiveness and remodeling are major features of asthma. We investigated whether pharmacological activation of the aryl hydrocarbon receptor (AhR) modifies these responses in a mixed allergen (MA) mouse model of asthma. MA exposure increased airway resistance, contractility, inflammation, and remodeling, with elevated AhR expression in whole lung and airway smooth muscle but limited canonical AhR target gene activation. Treatment with the high-affinity AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) improved lung mechanics, reduced inflammatory cell and cytokine accumulation, attenuated airway remodeling, and decreased airway narrowing in precision-cut lung slices. Bulk lung RNA sequencing further showed suppression of inflammatory, neutrophil-associated, and remodeling pathways following TCDD treatment, together with induction of canonical AhR target genes. Collectively, these findings demonstrate that AhR activation suppresses inflammatory gene networks, limits airway remodeling, and improves airway mechanics in experimental asthma, supporting the therapeutic potential of targeting AhR signaling to mitigate airway dysfunction and structural remodeling.