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Clara Cell RhoA Activation Aggravates Allergic Airway Inflammation by Disrupting Airway Barrier Integrity via Interstitial Macrophage Interaction

ABSTRACT: Background: Our previous research demonstrated that Ras homolog family member A (RhoA) activation in alveolar type 2 cells can prevent airway hyperresponsiveness and mitigate allergic airway inflammation. Objective: We aim to investigate the role of RhoA activation in larger airways, particularly Clara cells, during allergic airway inflammation and explore its underlying mechanisms. Methods: RhoA-deficient mice in Clara cells were generated by crossing CC10-CreERTM mice with RhoAfl/fl mice (CC10-CreERTM; RhoAfl/fl, RhoACKO). Airway epithelial barrier function was assessed by Trans-Epithelial Electrical Resistance (TEER) and permeability across Air-Liquid Interface (ALI) cultures. Multiparameter flow cytometry was applied to characterize various lung immune cells. Both bulk RNA sequencing (RNA-seq) and single-cell RNA sequencing (scRNA-seq) were also utilized. Results: Deletion of RhoA in Clara cells significantly reduced allergen-induced airway inflammation and remodeling. In vitro analysis demonstrated that airway epithelial cells from RhoACKO mice exhibited decreased TEER and increased permeability. multi-dimensional flow cytometry analysis revealed a significant reduction in interstitial macrophages (IMs) in RhoACKO mice compared to wild-type controls. Notably, scRNA-seq identified IMs as the most up-regulated population following cockroach allergen exposure. RNA-seq analysis revealed down-regulation of several genes, including Ccl24, IL-13, Mcpt1, and Tdo2. Integration of single-cell and bulk RNA-seq identified differentially expressed genes in IMs, such as Tlr1, Ccl24, Tmem26, and Msx3. Further experiments demonstrated that Ccl24 contributes to barrier damage, and blocking CCL24 attenuated allergic airway inflammation. Conclusion: This research underscores the importance of RhoA in Clara cells in airway inflammation and epithelial barrier integrity through regulating interstitial macrophage and its key mediator Ccl24.

ORGANISM(S): Mus musculus

PROVIDER: GSE283320 | GEO | 2025/12/31

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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Clara Cell RhoA Activation Aggravates Allergic Airway Inflammation by Disrupting Airway Barrier Integrity via Interstitial Macrophage Interaction

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