Review
Tuft cells in the pathogenesis of chronic rhinosinusitis with nasal polyps and asthma

https://doi.org/10.1016/j.anai.2020.10.011Get rights and content

Abstract

Objective

To review the latest discoveries regarding the role of tuft cells in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyposis and asthma.

Data Sources

Reviews and primary research manuscripts were identified from PubMed, Google, and bioRxiv using the search words airway epithelium, nasal polyposis, CRS or asthma and chemoreceptor cell, solitary chemosensory cell, brush cell, microvillus cell, and tuft cell.

Study Selections

Studies were selected on the basis of novelty and likely relevance to the functions of tuft cells in chronic inflammatory diseases in the upper and lower airways.

Results

Tuft cells coordinate a variety of immune responses throughout the body. After the activation of bitter-taste receptors, tuft cells coordinate the secretion of antimicrobial products by adjacent epithelial cells and initiate the calcium-dependent release of acetylcholine resulting in neurogenic inflammation, including mast cell degranulation and plasma extravasation. Tuft cells are also the dominant source of interleukin-25 and a significant source of cysteinyl leukotrienes that play a role in initiating inflammatory processes in the airway. Tuft cells have also been found to seem de novo in the distal airway after a viral infection, implicating these cells in dysplastic remodeling in the distal lung in the pathogenesis of asthma.

Conclusion

Tuft cells bridge innate and adaptive immunes responses and play an upstream role in initiating type 2 inflammation in the upper and possibly the lower airway. The role of tuft cells in respiratory pathophysiology must be further investigated, because tuft cells are putative high-value therapeutic targets for novel therapeutics in CRS with nasal polyps and asthma.

Introduction

Inflammatory diseases of the respiratory system—including chronic rhinosinusitis (CRS) and asthma affecting the upper and lower airway, respectively—have a major negative impact on the human population. The Centers for Disease Control and Prevention reports an 11.2% rhinosinusitis prevalence and a 7.6% asthma prevalence in the United States,1 which accounts for billions of dollars in health care spending annually, including almost 25% of annual adult antibiotic prescriptions.2, 3, 4 Within the last decade, it has been increasingly acknowledged that both CRS and asthma are heterogenous diseases characterized by a spectrum of inflammatory profiles that encompass distinct clinical presentations.5 Although type 2 inflammation often underlies CRS and asthma pathogenesis, recent genotypic, and molecular studies have revealed important new insights into the diverse cellular mechanisms driving these 2 clinical conditions. A broad spectrum of inflammatory profiles and endotypes is now appreciated in patients having CRS with and without nasal polyposis.6 Specifically, the role of rare epithelial cell types has recently been uncovered, especially tuft cells, which are members of the chemosensory family that include brush cells, microvillus cells (MVCs), and solitary chemosensory cells (SCCs). This review will focus on what is currently known regarding the functions of tuft cells in the airway, with specific regard to how tuft cells functionally bridge innate and adaptive responses that underlie type 2 inflammatory disease pathophysiology.

Section snippets

Rare Cell Types in the Respiratory Tract

The respiratory tract filters approximately 10,000 L of air each day and functions as an important barrier serving as a first line of defense against inspired airborne pathogens.7 A pseudostratified epithelium functions to initiate both innate and adaptive immune responses and undergo complex tissue regenerative processes that mediate tissue repair after infectious and noninfectious injury.8 Basal progenitor cells, ciliated cells, and secretory cells comprise most of the respiratory epithelium;

Characterizing Tuft Cells of the Airway

Tuft cells have been characterized in a wide variety of anatomic locations in humans, including the nasal cavity (both the respiratory and olfactory epithelia of the nose), pharynx, larynx, trachea, proximal airway, gastrointestinal tract (including the gastric mucosa, the small and large intestine, and the pancreatobiliary system), urethra and the murine thymic medulla, the auditory canals, and nasal aspects of the conjunctiva.19, 20, 21 Tuft cells are termed SCCs in the sinonasal and lung

Tuft Cells Coordinate Secretion of Antimicrobial Products and Facilitate Host Defense

Epithelial cells luminally secrete a broad collection of antimicrobial products that help promote homeostasis in the airway. Epithelial cells produce these compounds after activation of an array of pattern-recognition receptors, including C-type lectin receptors, NOD-like receptors, RIG-I-like receptors, and Toll-like receptors, although an overview of these receptors and pathways is beyond the scope of this review. Tuft cells are involved in these antimicrobial defenses and stimulate the

Acetylcholine Released by Tuft Cells Is Implicated in the Pathogenesis of Pulmonary Diseases

Early morphologic studies noted that tuft cells in the upper airways were densely supplied with nerve endings on their basolateral surface that were noted to be immunoreactive for calcitonin gene-related peptide and substance P.48 It was later found that murine brush cells in the trachea express markers not only of the bitter taste transduction system (T2Rs, PLCβ2, α-gustducin) but are also connected to cholinergic sensory nerve fibers. On stimulation, murine tuft cells in the trachea have been

Pathogenesis of Type 2 Inflammation in Chronic Rhinosinusitis With Nasal Polyps in the Upper Airway and Asthma in the Lower Airway

Chronic rhinosinusitis is classically differentiated into the following 2 types: with and without nasal polyps (CRS with nasal polyps [CRSwNP] and CRSsNP, respectively). Historically, CRSsNP was thought to be mediated at a cellular level by T-helper type 1 (TH1) inflammatory profile (interferon gamma) along with the TH3 inflammatory profile (IL-17) and CRSwNP by a type 2 inflammatory profile (IL-4, IL-5, IL-13); however, recently, CRS has increasingly been recognized as a spectrum of

Tuft cells Are the Dominant Source of IL-25, the Key Cytokine in the Initiation of Type 2 Inflammation

Tuft cells are known to constitutively secrete IL-25, which acts to sustain ILC2 homeostasis in the murine intestinal epithelium. On infection by helminths and in response to IL-4R activation24 and activation of the succinate receptor SUCNR1,37 tuft cells increase the production of IL-25, which triggers the production of IL-13 by ILC2s and ultimately resulting in increased frequencies of tuft and goblet cells.26,38 Similar to the intestinal epithelium, tuft cells in the human sinonasal

Tuft Cells Are Enriched in Human Nasal Polyp Tissue

The analysis of human sinonasal single-cell RNA sequencing data revealed that tuft cell markers are expressed at higher levels in the sinus than in the nasal cavity in patients with CRS, implicating tuft cells in the pathogenesis of CRSwNP.71 It was further illustrated that SCCs and brush cells proliferate on exposure to aeroallergens, including fungal extracts (Aspergillus fumigatus and Alternaria alternata)36,39 and after H1N1 influenza virus infection.72 Recently, a gustducin and

Tuft Cell–Derived Eicosanoids Contribute to Type 2 Inflammation

Cysteinyl leukotrienes are a subclass of eicosanoids that act as inflammatory mediators. Eicosanoids, including CysLT E4 (LTE4), are stable metabolites that have long been known to be increased in tracheal aspirates76,77 and urine78 of patients with asthma exacerbations. LTE4 has been found to cause airway constriction, plasma leakage, and eosinophil accumulation in the bronchial mucosa in humans.77 Initial investigations into the biosynthesis of LTE4 revealed that arachidonic acid is converted

Tuft Cells Are a Central Feature of Dysplastic Remodeling in the Distal Lung

Recently, the de novo appearance of tuft cells in the lower airway, specifically the distal mouse lung, has been observed after infection by an H1N1 influenza virus.72 H1N1 influenza virus infection resulted in widespread dysplastic alveolar remodeling that included the development of tuft cells in the distal lung. Subsequent activation of these tuft cells by stimulation with bitter-taste receptor agonists, succinate-triggered vasodilation, and plasma leakage potentially explain how childhood

Conclusion

Although the role of tuft cell lineages in promoting gastrointestinal type 2 responses is well established,21, 22, 23 their role in shaping respiratory pathophysiology is less well characterized. In chronic airway diseases such as CRSwNP and allergic asthma, further investigation on how airway tuft cells use gustatory signaling cascades to regulate the production of IL-25, CysLTs, and acetylcholine is necessary. Here, we propose new avenues for investigating respiratory tuft cell heterogeneity

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    Disclosures: N.A.C. has a patent pending for Therapy and Diagnostics for Respiratory Infection (61/697,652 [filed December 6, 2012] WO2013112865). All authors declare that they have no relevant conflicts of interest.

    Funding: This study was supported by the US Department of Veteran Affairs (Merit Award CX001617 to N.A.C.), the National Institutes of Health (NIH), National Institute on Deafness and Other Communication Disorders (NIDCD) (R01DC013588 to N.A.C) and the RLG Foundation, Inc. (to N.A.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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