Chemosensory Cell-Derived Acetylcholine Drives Tracheal Mucociliary Clearance in Response to Virulence-Associated Formyl Peptides

Perniss, Alexander; Liu, Shuya; Boonen, Brett; Keshavarz, Maryam; Ruppert, Anna-Lena; Timm, Thomas; Pfeil, Uwe; Soultanova, Aichurek; Kusumakshi, Soumya; Delventhal, Lucas; Aydin, Öznur; Pyrski, Martina; Deckmann, Klaus; Hain, Torsten; Schmidt, Nadine; Ewers, Christa; Günther, Andreas; Lochnit, Günter; Chubanov, Vladimir; Gudermann, Thomas; Oberwinkler, Johannes; Klein, Jochen; Mikoshiba, Katsuhiko; Leinders‐Zufall, Trese; Offermanns, Stefan; Schütz, Burkhard; Boehm, Ulrich; Zufall, Frank; Bufe, Bernd; Kummer, Wolfgang

doi:10.1016/j.immuni.2020.03.005

Cited by 77 publications

(130 citation statements)

References 93 publications

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“…intact cholinergic constriction evoked by electrical field stimulation. The effect of a formylated bacterial peptide on stimulating particle transport speed, however, was almost fully lost (Perniss et al 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Advillin is a tuft cell marker in the mouse alimentary tract

et al. 2020

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Tuft cells are a rare population of chemosensory cells at the mucosal surface epithelia of hollow organs. Their name-giving morphological feature is an apical tuft of stiff microvilli. Accordingly, the actin-binding protein, villin, was identified as one of the first tuft cell markers in immunohistochemical analysis. Unfortunately, villin expression is not restricted to tuft cells, but is also prominent e.g. in enterocytes, which limits the use of this gene as a marker and as an experimental tool to genetically target tuft cells. Here, we report that the villin-related protein, advillin, is a specific tuft cell marker in the gastro-intestinal and biliary tract epithelia. In situ hybridization and immunohistochemistry revealed that advillin expression, unlike villin, was restricted to solitary cholinergic tuft cells in the mucosal linings of the small and large intestine, and in the gall bladder. In the glandular stomach, villin and advillin mRNA were present in all epithelial cells, while detectable protein levels were confined to solitary tuft cells. Advillin expression was no longer detectable in the mucosa of the intestinal and biliary tract from Pou2f3 deficient mice that lack tuft cells. Finally, crossing Avil-Cre transgenic mice with a double-fluorescent reporter mouse line resulted in specific targeting of gastro-intestinal and biliary tuft cells. Our analysis introduces advillin as a selective marker and tool in histological and functional analysis of the alimentary tract tuft cell system. Electronic supplementary material The online version of this article (doi:10.1007/s10735-020-09893-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Advillin is a tuft cell marker in the mouse alimentary tract

et al. 2020

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“…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 ).…”

Section: Pathophysiological Roles Of Ach Produced By Tuft Cellsmentioning

confidence: 99%

“…The administration of high concentration of atropine inhibiting ASM constriction was a non-specific effect and the inhibitory effect of atropine did not indicate that serotonin-induced ASM constriction was in a muscarinic receptor-independent manner. Secondly, another nonnegligible reason is the different situations between trachea and bronchi that cholinergic chemosensory cells exist in the tracheal rather than bronchial mucosa ( Krasteva et al, 2012a ; Perniss et al, 2020 ). Epithelial cell has been identified a source of ACh in the airways, we should not exclude the possibility that epithelial cells-derived ACh participated in ASM constriction.…”

Section: Pathophysiological Roles Of Ach Produced By Tuft Cellsmentioning

confidence: 99%

“…The sources of ACh in the lung are intricate that both parasympathetic nerves and other non-neuronal cells such as tuft cells can contribute to the release of ACh. Trpm5 -deficient mice that lack tuft cells are more susceptible to infection, suggesting that tuft cells participate in airway anti-infections ( Perniss et al, 2020 ).…”

Section: Potential Clinical Applicationmentioning

confidence: 99%

“…Tiotropium, a long-lasting non-specific muscarinic antagonist, significantly inhibited the accumulation of eosinophils and Th2 inflammation, and antagonized the proliferation of fibroblasts and myofibroblasts, thus eliminating the airway remodeling in asthma and chronic obstructive pulmonary disease (COPD) ( Bos et al, 2007 ; Pieper et al, 2007 ). In sputum from patients with COPD, formylated bacterial peptides have been detected and tuft cells have been reported to sense virulence-associated formyl peptides and release ACh to activate tracheal mucociliary clearance ( Perniss et al, 2020 ). In another study of COPD, the authors found that tiotropium could reduce IL-17A induced CXCL8 release and eliminate inflammation, indicating the potential of anti-cholinergic therapy in controlling COPD ( Meurs et al, 2013 ).…”

Section: Potential Clinical Applicationmentioning

confidence: 99%

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

Pan

Zhang

Shao

et al. 2020

Front. Cell Dev. Biol.

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Tuft cells, rare solitary chemosensory cells, are distributed in mucosal epithelium throughout mammalian organs. Their nomenclatures are various in different organs and may be confused with other similar cells. Current studies mainly focus on their chemosensory ability and immune functions in type 2 inflammation. Several state-of-the-art reviews have already systematically discussed their role in immune responses. However, given that tuft cells are one of the crucial components of non-neuronal cholinergic system, the functions of tuft cell derived acetylcholine (ACh) and the underlying mechanisms remain intricate. Existing evidence demonstrated that tuft cell derived ACh participates in maintaining epithelial homeostasis, modulating airway remodeling, regulating reflexes, promoting muscle constriction, inducing neurogenic inflammation, initiating carcinogenesis and producing ATP. In this review, the ACh biosynthesis pathways and potential clinical applications of tuft cells have been proposed. More importantly, the main pathophysiological roles and the underlying mechanisms of tuft cell derived ACh are summarized and discussed.

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Bitter taste receptors in the reproductive system: Function and therapeutic implications

Lu,

Moore Simas,

Delpapa

et al. 2024

Journal Cellular Physiology

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Type 2 taste receptors (TAS2Rs), traditionally known for their role in bitter taste perception, are present in diverse reproductive tissues of both sexes. This review explores our current understanding of TAS2R functions with a particular focus on reproductive health. In males, TAS2Rs are believed to play potential roles in processes such as sperm chemotaxis and male fertility. Genetic insights from mouse models and human polymorphism studies provide some evidence for their contribution to male infertility. In female reproduction, it is speculated that TAS2Rs influence the ovarian milieu, shaping the functions of granulosa and cumulus cells and their interactions with oocytes. In the uterus, TAS2Rs contribute to uterine relaxation and hold potential as therapeutic targets for preventing preterm birth. In the placenta, they are proposed to function as vigilant sentinels, responding to infection and potentially modulating mechanisms of fetal protection. In the cervix and vagina, their analogous functions to those in other extraoral tissues suggest a potential role in infection defense. In addition, TAS2Rs exhibit altered expression patterns that profoundly affect cancer cell proliferation and apoptosis in reproductive cancers. Notably, TAS2R agonists show promise in inducing apoptosis and overcoming chemoresistance in these malignancies. Despite these advances, challenges remain, including a lack of genetic and functional studies. The application of techniques such as single‐cell RNA sequencing and clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR‐associated endonuclease 9 gene editing could provide deeper insights into TAS2Rs in reproduction, paving the way for novel therapeutic strategies for reproductive disorders.

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Chemosensory Cell-Derived Acetylcholine Drives Tracheal Mucociliary Clearance in Response to Virulence-Associated Formyl Peptides

Cited by 77 publications

References 93 publications

Advillin is a tuft cell marker in the mouse alimentary tract

Advillin is a tuft cell marker in the mouse alimentary tract

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

Bitter taste receptors in the reproductive system: Function and therapeutic implications

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