Abstract Rationale Airway hyperresponsiveness and remodeling represent the principal structural and functional hallmarks of asthma, driving excessive airway narrowing and resistance to airflow. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that functions as a cellular sensor of environmental and endogenous molecules. Our recent studies showed an increased AhR expression in the airways of asthmatics, and its activation inhibits inflammation-induced changes in mitochondrial dynamics in vitro. However, the role of AhR activation in regulating the pathophysiology of asthma in whole-body physiology is not yet fully understood. In the present study, we investigated the in vivo activation of AhR in modulating airway hyperresponsiveness and remodeling in a mixed allergen (MA)-induced mouse model of asthma. Methods Wild-type C57BL/6J (male and female) mice were obtained from the Jackson Laboratory and challenged intranasally with MA (10 μg each of ovalbumin, Alternaria alternata, Aspergillus fumigatus and Dermatophagoides farin) or phosphate-buffered saline (PBS) for four weeks. On alternate days, animals were also administered with AhR agonist TCDD (10 μg/kg). Lung mechanics were assessed using the flexiVent system (SCIREQ). Subsequently, bronchoalveolar lavage (BAL) fluid was collected for differential leukocyte count and cytokine analyses, while lung tissues were processed for histological and molecular evaluations. Results MA-challenged mice exhibited significantly increased airway resistance (Rrs) and elastance (Ers), along with a reduction in compliance (Crs), compared to PBS controls. TCDD treatment attenuated these MA-induced alterations in lung function. MA exposure also induced significant immune cell infiltration and upregulation of proinflammatory cytokines in BAL fluid. This was accompanied by notable airway remodeling, marked by enhanced smooth muscle mass and increased expression of remodeling-associated proteins such as collagen-I, vimentin, and α-SMA. These pathological and biochemical changes were substantially mitigated by TCDD exposure. Immunoblotting and RT-qPCR analyses revealed elevated AhR expression in MA-challenged mice lungs relative to PBS. Immunofluorescence and laser capture microdissection (LCM) analyses revealed that AhR expression was localized and upregulated within ASM layer of MA-challenged mice lungs compared to PBS controls. Moreover, LCM-isolated ASM showed increased Cyp1b1 mRNA expression following TCDD treatment, confirming AhR activation. Conclusion Overall, these findings indicate that AhR activation attenuates MA-induced airway hyperresponsiveness and remodeling, underscoring a protective role for AhR signaling in asthma pathogenesis. This abstract is funded by: NIH grants R01-HL171245 (Venkatachalem and Britt), R01-HL146705 (Venkatachalem), R01-HL155095 (Britt)
Reza et al. (Fri,) studied this question.