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Allergen-Induced Epithelial Senescence Drives Airway Inflammation via the AhR-c-Myc Axis

ABSTRACT: Background: Environmental allergens can induce epithelial cellular senescence, which contributes to airway inflammation. The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor responsive to environmental stimuli, may regulate this process. Objectives: We sought to determine whether epithelial AhR controls cellular senescence and to define its underlying mechanisms in allergic airway inflammation. Methods: Club cell-specific p16 conditional knockout mice (p16ΔScgb1a1) were used to assess the role of epithelial senescence and allergic airway inflammation. AhR regulation of senescence was examined using AhR agonist, antagonist, and Club cell-specific AhR-deficient mice (AhRΔScgb1a1) in both in vitro and in vivo models. Bulk RNA-seq was performed to identify AhR-regulated, senescence-associated genes, and immunoprecipitation (IP) along with ChIP-PCR was employed to validate AhR-target gene interactions. Results: Single-cell transcriptomics revealed epithelial senescence as a key feature of allergen-induced asthma. p16ΔScgb1a1 mice exhibited reduced cockroach allergen–induced airway inflammation and decreased Th2/Th17 cytokines in bronchoalveolar lavage fluids (BALFs). AhR signaling was enhanced in airway epithelial cells of allergen-treated asthmatics and regulated senescence, as indicated by SA-β-gal activity and expression of Cdkn2a, Cdkn1a, and γH2AX. The AhR agonist VAF347 suppressed, whereas AhRΔScgb1a1 deficiency exacerbated, airway inflammation. RNA-seq identified senescence as a major AhR-regulated pathway, highlighting c-Myc, TGF-β2, IGFBP3, and SERPINE1 as key targets. AhR binding to the c-Myc promoter was validated, and c-Myc inhibition with EN4 reduced allergen-induced senescence and inflammation. Conclusions: Epithelial AhR suppresses allergen-induced senescence and airway inflammation through direct regulation of c-Myc. These findings establish the AhR–c-Myc axis as a potential therapeutic target in allergic asthma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313889 | GEO | 2026/03/05

REPOSITORIES: GEO

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Project description:Rationale: Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has been considered as an important regulator for immune diseases. We have previously shown that AhR protects against allergic airway inflammation. The underlying mechanism, however, remains undetermined. Objectives: We sought to determine whether AhR specifically in Type II alveolar epithelial cells (AT2) modulates allergic airway inflammation and its underlying mechanisms. Methods: The role of AhR in AT2 cells in airway inflammation was investigated in a mouse model of asthma with AhR conditional knock out mice in AT2 cells (Sftpc-Cre;AhRflox/flox). The effect of AhR on allergen-induced autophagy was examined by both in vivo and in vitro analyses. The involvement of autophagy in airway inflammation was analyzed by using autophagy inhibitor chloroquine. The AhR-regulated gene profiling in AT2 cells was also investigated by RNA-seq analysis. Results: Sftpc-Cre; AhRflox/flox mice showed exacerbation of allergen-induced airway hyperresponsiveness and airway inflammation with elevated Th2 and airway epithelial-derived cytokines in bronchoalveolar lavage fluid (BALF). Notably, an increased allergen-induced autophagy was observed in the lung tissues of Sftpc-Cre; AhRflox/flox mice when compared with wild-type mice. Further analyses suggested a functional axis of AhR-TGF-β1 that is critical in driving allergic airway inflammation through regulating allergen-induced cellular autophagy. Furthermore, inhibition of autophagy suppressed allergic airway inflammation with decreased Th2 and epithelial cell-derived cytokines in BALFs. Additionally, RNA-seq analysis suggests that autophagy is one of the major pathways and CALCOCO2/NDP52 and S1009 are major autophagy-associated genes in AT2 cells that contribute to the AhR-mediated allergic airway inflammation. Conclusion: These results suggest that AhR in AT2 cells functions as a protective mechanism against allergic airway inflammation through controlling cell autophagy.

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Allergen-Induced Epithelial Senescence Drives Airway Inflammation via the AhR-c-Myc Axis

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