Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling

Monika I. Hollenhorst, Innokentij Jurastow, Rajender Nandigama, Silke Appenzeller, Lei Li, Jörg Vogel, Stephanie Wiederhold, Mike Althaus, Martin Empting, Janine Altmüller, Anna K.H. Hirsch, Veit Flockerzi, Brendan J. Canning, Antoine Emmanuel Saliba, Gabriela Krasteva-Christ

Research output: Contribution to journalArticle

Abstract

For protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter “taste” substances are most probably initiated by tracheal brush cells (BC). Our single-cell RNA-seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5). We directly demonstrate the secretion of acetylcholine (ACh) from BC upon stimulation with the Tas2R agonist denatonium. Inhibition of the taste transduction cascade abolished the increase in [Ca2+]i in BC and subsequent ACh-release. ACh-release is regulated in an autocrine manner. While the muscarinic ACh-receptors M3R and M1R are activating, M2R is inhibitory. Paracrine effects of ACh released in response to denatonium included increased [Ca2+]i in ciliated cells. Stimulation by denatonium or with Pseudomonas quinolone signaling molecules led to an increase in mucociliary clearance in explanted tracheae that was Trpm5- and M3R-mediated. We show that ACh-release from BC via the bitter taste cascade leads to immediate paracrine protective responses that can be boosted in an autocrine manner. This mechanism represents the initial step for the activation of innate immune responses against pathogens in the airways.

Original languageEnglish (US)
Pages (from-to)316-332
Number of pages17
JournalFASEB Journal
Volume34
Issue number1
DOIs
StatePublished - Jan 1 2020

Keywords

  • acetylcholine
  • brush cells
  • mucociliary clearance
  • single-cell RNA-seq
  • taste

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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  • Cite this

    Hollenhorst, M. I., Jurastow, I., Nandigama, R., Appenzeller, S., Li, L., Vogel, J., Wiederhold, S., Althaus, M., Empting, M., Altmüller, J., Hirsch, A. K. H., Flockerzi, V., Canning, B. J., Saliba, A. E., & Krasteva-Christ, G. (2020). Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling. FASEB Journal, 34(1), 316-332. https://doi.org/10.1096/fj.201901314RR