Flagellin shifts 3D bronchospheres towards mucus hyperproduction
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Open Access
Flagellin shifts 3D bronchospheres towards mucus hyperproduction Richard F. Sprott1†, Felix Ritzmann1†, Frank Langer2, Yiwen Yao1, Christian Herr1, Yvonne Kohl3, Thomas Tschernig4, Robert Bals1† and Christoph Beisswenger1*†
Abstract Cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) are associated with acute and chronic bacterial infections of the lung. Excessive differentiation of basal cells to mucus-producing goblet cells can result in mucus hyperproduction and loss of mucociliary clearance in the airways of CF and COPD patients. Here, we aimed to investigate the effect of pathogen-associated molecular patterns (PAMPs) on the differentiation of human 3D bronchospheres. Primary human bronchial epithelial cells (HBECs) were differentiated to bronchospheres in the presence of bacterial flagellin and LPS and the synthetic Toll-like receptor (TLR) ligands Pam3CSK4 (TLR-2) and polyinosinic:polycytidylic acid (pIC, TLR-3). Electron and fluorescence microscopy showed that the differentiation of bronchospheres associated with the formation of lumina and appearance of cilia within 30 days after seeding. Incubation with flagellin resulted in a decreased formation of lumina and loss of cilia formation. Incubation with Pam3CSK, pIC, and LPS did not significantly affect formation of lumina and ciliation. Mucus production was strongly increased in response to flagellin and, to a lesser degree, in response to Pam3CSK4. Our results indicate that bacterial factors, such as flagellin, drive the differentiation of the respiratory epithelium towards mucus hyperproduction. Keywords: Organoids, Bronchospheres, Mucus, PAMPs, Flagellin
Introduction Airway remodeling contributes to air flow limitation and loss of lung structure in chronic respiratory diseases, such as CF and COPD. In both diseases, basal and goblet cell hyperplasia leads to mucus hyperproduction, loss of mucociliary clearance, disturbed epithelial barrier function, and impaired regeneration of the airway epithelium [1, 2]. Therefore, the respiratory epithelium is a potential target for therapeutic intervention addressing basal cell differentiation and mucus hyperproduction [1].
* Correspondence: [email protected] † Richard F. Sprott, Felix Ritzmann, Robert Bals and Christoph Beisswenger contributed equally to this work. 1 Department of Internal Medicine V – Pulmonology, Allergology and Respiratory Critical Care Medicine, Saarland University, Kirrberger Str. 100, Building 41M, 66421 Homburg/Saar, Germany Full list of author information is available at the end of the article
CF patients suffer from persistent bacterial infections of the lung with Pseudomonas aeruginosa being a dominant pathogen later in life [3]. In COPD, nontypeable Haemophilus influenzae (NTHi) contributes to pulmonary inflammation and acute exacerbations [4]. Infections and colonization in the lung with these pathogens associate with a constant contact of the airway epithelium with PAMPs (e.g. lipopeptide, LPS, flagellin) which activat
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