Abstract
Repetitive aeroallergen exposure is linked to sensitization and airway remodeling through incompletely understood mechanisms. In this study, we examine the dynamic mucosal response to cat dander extract (CDE), a ubiquitous aero-allergen linked to remodeling, sensitization and asthma. We find that daily exposure of CDE in naïve C57BL/6 mice activates innate neutrophilic inflammation followed by transition to a lymphocytic response associated with waves of mucosal transforming growth factor (TGF) isoform expression. In parallel, enhanced bronchiolar Smad3 expression and accumulation of phospho-SMAD3 was observed, indicating paracrine activation of canonical TGFβR signaling. CDE exposure similarly triggered epithelial cell plasticity, associated with expression of mesenchymal regulatory factors (Snai1 and Zeb1), reduction of epithelial markers (Cdh1) and activation of the NFκB/RelA transcriptional activator. To determine whether NFκB functionally mediates CDE-induced growth factor response, mice were stimulated with CDE in the absence or presence of a selective IKK inhibitor. IKK inhibition substantially reduced the level of CDE-induced TGFβ1 expression, pSMAD3 accumulation, Snai1 and Zeb1 expression. Activation of epithelial plasticity was demonstrated by flow cytometry in whole lung homogenates, where CDE induces accumulation of SMA+Epcam+ population. Club cells are important sources of cytokine and growth factor production. To determine whether Club cell innate signaling through NFκB/RelA mediated CDE induced TGFβ signaling, we depleted RelA in Secretoglobin (Scgb1a1)-expressing bronchiolar cells. Immunofluorescence-optical clearing light sheet microscopy showed a punctate distribution of Scgb1a1 progenitors throughout the small airway. We found that RelA depletion in Secretoglobin+ cells results in inhibition of the mucosal TGFβ response, blockade of EMT and reduced subepithelial myofibroblast expansion. We conclude that the Secretoglobin—derived bronchiolar cell is central to coordinating the innate response required for mucosal TGFβ1 response, EMT and myofibroblast expansion. These data have important mechanistic implications for how aero-allergens trigger mucosal injury response and remodeling in the small airway.
Highlights
Allergic asthma (AA) is a global health concern for 235 million people worldwide [1] who are affected by consequences of airway remodeling, Th2 polarization and eosinophilia [2]
cat dander extract (CDE) induces waves of inflammation and mucosal transforming growth factor β (TGFβ) isoform expression the induction of airway inflammation-remodeling in response to protease-encoded aero-allergens is known, little is known about early steps in the initiation of CDE-induced remodeling
Previous work using house dust mite (HDM) has shown that inducible epithelial TGFβ1 expression plays an important role in expansion of a population of luminal innate lymphoid cells (ICL)2s, linked to airway hyperreactivity and sensitization [27]
Summary
Allergic asthma (AA) is a global health concern for 235 million people worldwide [1] who are affected by consequences of airway remodeling, Th2 polarization and eosinophilia [2]. A body of work has shown that aero-allergens are plant and animal-derived products that modify the epithelial barrier function and activate innate signaling cascades [9]. The Dermatophagtoides-produced cysteine protease allergen, Der p1, disrupts epithelial tight junctions by cleavage of zona occludens, and activates release of pro-inflammatory cytokines by epithelial cells and plasticity [12]. The alkaline protease 1 (Alp1) is an Aspergillus spp.-derived aeroallergen that disrupts epithelial tight junctions by cleaving epithelial cadherin, disrupting barrier function, producing IL33/ CCL2 secretion and eosinophilia [17]. These distinct aero-allergens induce mucosal signaling by selfcontained enzymatic activity triggering epithelial expression of DC and neutrophil activating cytokines
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