Cholinergic neurotransmission links solitary chemosensory cells to nasal inflammation

Abstract

Solitary chemosensory cells (SCCs) of the nasal cavity are specialized epithelial chemosensors that respond to irritants through the canonical taste transduction cascade involving Gα-gustducin and transient receptor potential melastatin 5. When stimulated, SCCs trigger peptidergic nociceptive (or pain) nerve fibers, causing an alteration of the respiratory rate indicative of trigeminal activation. Direct chemical excitation of trigeminal pain fibers by capsaicin evokes neurogenic inflammation in the surrounding epithelium. In the current study, we test whether activation of nasal SCCs can trigger similar local inflammatory responses, specifically mast cell degranulation and plasma leakage. The prototypical bitter compound, denatonium, a well-established activator of SCCs, caused significant inflammatory responses in WT mice but not mice with a genetic deletion of elements of the canonical taste transduction cascade, showing that activation of taste signaling components is sufficient to trigger local inflammation. Chemical ablation of peptidergic trigeminal fibers prevented the SCC-induced nasal inflammation, indicating that SCCs evoke inflammation only by neural activity and not by release of local inflammatory mediators. Additionally, blocking nicotinic, but not muscarinic, acetylcholine receptors prevents SCC-mediated neurogenic inflammation for both denatonium and the bacterial signaling molecule 3-oxo-C12-homoserine lactone, showing the necessity for cholinergic transmission. Finally, we show that the neurokinin 1 receptor for substance P is required for SCC-mediated inflammation, suggesting that release of substance P from nerve fibers triggers the inflammatory events. Taken together, these results show that SCCs use cholinergic neurotransmission to trigger peptidergic trigeminal nociceptors, which link SCCs to the neurogenic inflammatory pathway.rhinitis | innate immunity | quorum sensing | chemesthesis | airway irritation

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

“…Furthermore, in vivo studies demonstrated that mice exposed to acyl-homoserine lactones via the retronasal stream experienced significant reductions in respiratory rate, suggesting that interactions between bacterial acyl-homoserine lactones and chemosensory cells are capable of inducing responses indicative of nasal trigeminal irritants (304). The activation of nasal solitary chemosensory cells by acyl-homoserine lactones triggers a proinflammatory response (328); this response may damage the integrity of the epithelium and enable bacteria to access the trigeminal nerve endings. Once bacteria have penetrated the epithelium, they may potentially travel along the olfactory and/or trigeminal nerves to the brain, within axons, between the axons, within the surrounding glia (olfactory ensheathing cells or Schwann cells), or between the glia and the connective tissue sheath (perineurium) that contains the nerve bundle.…”

The Role of Taste Receptors in Airway Innate Immune Defense

“…However, while the expression of taste receptors in the sinonasal epithelium is ubiquitous on disparate cell types, including ciliated cells and solitary chemosensory cells, in the tongue taste receptor expression is confined to type II cells within the taste buds. Furthermore, while some bitter taste receptors in the airway are upstream of a nervous signaling cascade, others act in a cell-autonomous fashion only [8,19,20]. When a ligand binds to a taste GPCR, there is activation of phospholipase C isoform β2 (PLCB2), which triggers downstream inositol 1,4,5-trisphosphate (IP3) production.…”

“…These cells are immunoreactive with α-gustducin, a taste signalling component, and they share many similarities with taste bud cells [28]. Because of their rarity, they are difficult to isolate experimentally [19]. Solitary chemosensory cells express both sweet and bitter taste receptors that are capable of responding to a variety of compounds [8,20,27,56,57].…”

“…In response to bitter stimulation, these cells do not activate NO production, but instead mediate a separate cohort of responses. In mouse SCCs, the calcium response resulting from bitter taste receptor stimulation causes acetylcholine (ACh) release that has breath holding effects and also results in downstream inflammatory mediator release [8,19,20]. Both of these responses are at least partially immunomodulatory in nature: breath holding limits toxin or organism aspiration, while inflammatory mediators often participate in a larger immune signaling cascade.…”

Nasal Chemesthesis: Similarities Between Humans and Rats Observed in In Vivo Experiments

“…Utilizing receptors and signaling cascades classically associated with the detection of bitter tastants, SCCs effectively enhance the chemosensory repertoire of the TN, facilitating its indirect activation by hydrophilic compounds that cannot readily cross epithelial layers to reach chemosensitive TN fibers. These specialized cells are present in functionally relevant areas of the respiratory epithelia of humans and rodents, where they respond to irritants and bacterial metabolites, trigger respiratory and other responses, and excite TN fibers upon activation (Saunders et al 2014;Barham et al 2013;Tizzano et al 2010;Finger et al 2003).…”