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

Abstract

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractFor 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 [Ca 2+ ] i in | 317 HOLLENHORST ET aL.

Acetylcholine From Tuft Cells: The Updated Insights Beyond Its Immune and Chemosensory Functions

“…However, the biosynthesis and release of ACh in tuft cells remains largely unknown. So far, only the expression of ChAT on tuft cells, and the release of ACh from tuft cells have been experimentally validated ( Ting and von Moltke, 2019 ; Hollenhorst et al, 2020 ). On account of the absence of VAChT and CHT1 in gastrointestinal tuft cells, we highly deduce that, except the canonical biosynthesis pathway of ACh, tuft cells may synthesize and release ACh through different pathways ( Figure 1 ).…”

“…The oscillation of elevated Ca 2+ levels subsequently promotes the release of ACh ( Fu et al, 2018 ). However, bitter and other diverse substances, whether noxious or innocuous, trigger ACh biosynthesis of tuft cells via canonical taste transduction cascade depended on gustducin and TRPM5 ( Saunders et al, 2014 ; Hollenhorst et al, 2020 ). This phenomenon could only be seen in the nasal epithelium.…”

“…This phenomenon could only be seen in the nasal epithelium. The inhibition of the taste transduction signaling abolished the elevated Ca 2+ levels and subsequent ACh-release in mice ( Hollenhorst et al, 2020 ). On the contrary, the activation of taste transduction increased the release of tuft cells derived ACh, and this neurotransmitter interacted with receptors on nerve fiber terminal to evoke nerve fibers-related inflammation and trigger protective reflexes ( Krasteva et al, 2011 ).…”

“…The evocation of respiratory reflexes reflected on the sharp changes in respiration combined with abrupt decreases in respiratory rate. Apart from the bitter substances, tuft cells are also capable of detecting bacterial products in airway lining fluid and thus conduct mucociliary clearance ( Krasteva et al, 2012a ; Hollenhorst et al, 2020 ; Perniss et al, 2020 ). Using Avil cre :Chat fl/fl mouse model which retained neural cholinergic signaling but conditional loss of ACh synthesis in tuft cells, Perniss et al demonstrated that by detecting formylated bacterial peptides, tuft cells rather than cholinergic nerves released ACh activating mucociliary clearance ( Perniss et al, 2020 ).…”

Nicotine stimulates ion transport via metabotropic β4 subunit containing nicotinic ACh receptors

“…In previous studies, we found a role for ACh released from non‐neuronal sources as a regulator of airway epithelial ion transport (Hollenhorst, Lips, Weitz, et al, 2012; Hollenhorst, Lips, Wolff, et al, 2012). Since the first studies of the non‐neuronal cholinergic system about 20 years ago (Grando, 1997; Sato et al, 1999; Wessler, Kirkpatrick, & Racké, 1998), it is now well established that ACh plays an important role as autocrine and paracrine signalling molecule in diverse non‐neuronal tissues, including the airway epithelium (Hollenhorst et al, 2020; Perniss, Liu, et al, 2020). ACh transmits its signals via two different classes of receptors: muscarinic (M) receptors and nicotinic receptors (nAChRs) (Lustig, 2006).…”