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

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.

Figure 1.

Tuft cells bridge innate and adaptive immune responses. On stimulation by bitter agonists, tuft cells coordinate the release of antimicrobial peptides by neighboring ciliated epithelial cells. Tuft cells are also known to stimulate local inflammation through the release of IL-25 and CysLTs that can stimulate ILC2 and downstream pathways leading to the release of IL-13, IL-5, and initiating type 2 inflammation. IL-13 also feedbacks on tuft cells, resulting in expansion. In the upper airway, tuft cells are also intimately innervated by free nerve fibers of the trigeminal nerve and induce neurogenic inflammation through the release of acetylcholine, stimulating associated nerve fibers to release peptidergic neurotransmitters. CysLTs, cysteinyl leukotrienes; IL, interleukin; ILC2, innate lymphoid group 2 cells.

Figure 2.

Phenotypes and Endotypes of CRS. The asterisk indicates relation to AERD, a unique clinical phenotype of CRSwNP associated with both asthma and intolerance to COX 1–inhibiting agents.^,,, AERD, aspirin-exacerbated respiratory disease; COX-1, cyclooxygenase-1; CRS, chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps; IFNγ, interferon gamma; IL, interleukin; ILC, innate lymphoid cells; T_H, T-helper.