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Airway brush cells: Not as “tuft” as you might think

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Science Immunology  05 Oct 2018:
Vol. 3, Issue 28, eaau8719
DOI: 10.1126/sciimmunol.aau8719

Abstract

The leukotriene E4 receptor CysLT3R regulates expansion of chemosensory brush cells and production of interleukin-25 in the airways.

A rare population of specialized taste-chemosensory intestinal epithelial cells called tuft cells are key inducers of type 2 immune responses through their release of interleukin-25 (IL-25) (13). The role of such cells in the airways has yet to be fully elucidated. In this issue of Science Immunology, Bankova et al. report that brush cells are the main source of IL-25 in the airways and that their expansion is controlled by the cysteinyl leukotriene receptor 3 (CysLT3R) (4).

Mucosal tissues are constantly exposed to the environment and form our first layer of defense and decision-making upon contact with pathogens and allergens. Brush cells, similar to tuft cells, are chemosensory epithelial cells that express elements of the bitter taste transduction system. They are found in the trachea and proximal bronchi, often intertwined with nerve fibers. Up to now, their phenotype and function have been poorly defined, although their location in the airways, their proximity to nerves, and their rapid responsiveness point toward a powerful role for this rare cell type (5).

The importance of epithelial-derived cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) in instigating type 2 immune responses is well established, although the specific cellular origin of these factors is still being unraveled. The discovery of the production of IL-25 by tuft cells in the intestine (13) begged the question as to whether chemosensory cells in other mucosal sites would also be the primary source of IL-25 and, indeed, other cytokines associated with epithelial cell responses.

Bankova et al. demonstrate that brush cells in the airways are distinct from other epithelial or immune cells in this mucosal compartment and have a transcriptional signature close to that of intestinal tuft cells (sharing 74 of 94 genes that compose the consensus intestinal tuft cell signature). Among the 20 unshared genes, a few were not expressed at all in airway brush cells, suggesting some specificity between different mucosal tissues (4). For example, free fatty acid receptor 3 (or GPR41), a receptor for short-chain fatty acids, was not expressed in airway brush cells, as might be expected given the predominant production of these metabolites by bacterial fermentation in the gut. However, importantly, similar to intestinal tuft cells, brush cells were found to be the main IL-25–expressing cells of the airways, which mediate ILC2 (group 2 innate lymphoid cell)–dependent inflammation after allergen inhalation (Fig. 1). A recent publication by Kohanski et al. (6) reported that solitary chemosensory cells (SCCs) are likely to be the primary source of IL-25 in human nasal epithelium. In patients with chronic rhinosinusitis, the number of SCCs was increased in nasal polyps, and in vitro exposure to IL-13 increased SCC numbers and production of IL-25. Similar to the brush cells characterized by Bankova et al., SCCs express the taste-associated G protein gustducin and the intestinal tuft cell marker doublecortin-like kinase 1. Given the strong similarities between the airway brush cells characterized in mice and the nasal SCCs from humans, there is the enticing possibility that these are the same or closely related cells, which could be targets for future therapies. Certainly, further investigation of the phenotype, function, and gene expression profile of brush cells in humans is warranted.

Fig. 1 LTE4 drives brush cell expansion and type 2 inflammation in the airways.

Chemosensory brush cells, a rare airway epithelial cell type, are activated by LTE4 through CysLT3R stimulation after allergen inhalation. Upon activation, they release IL-25, which triggers inflammatory ILC2 recruitment and activation. The inflammatory ILC2s in turn release IL-13, which promotes goblet cell hyperplasia, mucus secretion, and eosinophil activation. Brush cells either further expand in response to IL-13 production—as do their intestinal counterparts, the tuft cells—or expand directly through an LTE4-dependent but STAT6-independent pathway.

Credit: Adapted by A. Kitterman/Science Immunology

The particularly novel finding from the Bankova et al. study is the link between leukotrienes (LTs) and the activation of brush cells (4). The link between LTs and type 2 airway inflammation is well established, with cysteinyl LTs (LTC4, LTD4, and LTE4) being potent mediators of allergic disease. LTs are arachidonic acid metabolites, further processed to LTA4 by 5-lipoxygenase. They can act on various cells, inducing inflammation, contraction of smooth muscle, chemokine production, and permeabilization of the vasculature. Cysteininyl LTs receptor 1 inhibitors are currently in development and in clinical trial for treatment of asthma (7). Intriguingly, Bankova et al. showed that brush cell expansion, although driven by IL-25, is not solely dependent on IL-13 and signal transducer and activator of transcription 6 (STAT6) signaling, as has been reported for intestinal tuft cells (4). Rather, they show that this expansion is controlled by LTE4 and its specific receptor on brush cells, CysLT3R (Fig. 1). LTE4, contrary to other LTs, cannot activate ILC2s directly, as demonstrated in vitro (3), but LTE4 administration in vivo does cause ILC2 expansion and activation. Bankova et al. show that chronic administration of LTE4 itself is sufficient to trigger IL-25 release by brush cells and their expansion in a STAT6-independent manner (4). Thus, ILC2s and their release of IL-13 are central components of the inflammatory process; however, they are not essential for brush cell functionality. This might explain how airway remodeling in asthma or other chronic airway inflammatory diseases could develop independently of IL-13 signaling.

Several ILC2 subpopulations can be distinguished with a continuum between the inducible or inflammatory ILC2s (iILC2s, responsive to IL-25) and natural ILC2s (nILC2s) residing principally in the mucosal barrier and being responsive to IL-33 (8). Intriguingly, chronic exposure to LTE4 caused expansion of both populations, although only the iILC2 induction was IL-25–dependent. Whether brush cells are responsible for the nILC2 expansion remains an open question. Interestingly, the authors show by means of bulk RNA sequencing (RNA-seq) analysis that airway brush cells do not express IL-33 or its receptor ST2 but do express TSLP, raising the possibility that the latter might be responsible for the activation of nILC2s. Although the full pathway of ILC2 activation after LTE4 is not yet clear, this observation highlights how multiple circuits exist to ensure optimal activation of ILC2s and consequently inflammatory responses after aeroallergen inhalation.

Further challenges in this nascent field are to determine how pathogens or allergens are “sensed” by chemosensory cells and whether “bitter-tasting,” which causes release of acetylcholine and activation of nearby vagal nerve fibers, is involved in this process. A fuller understanding as to whether LTs (such as LTE4 binding to CysLT3R) can trigger the activation of the gustatory transduction system in brush cells could open important avenues of research. The authors have previously reported a role for mast cells and dendritic cells in the production of LTE4 after Alternaria stimulation (9), and it will be important to determine whether an immune cell is indeed producing LTE4 upstream of the brush cells, the latter serving as a refiner of the inflammatory response rather than as an initiator. Another further possibility is that the brush cells recognize aeroallergens through specific receptors and activate themselves in an autocrine manner; indeed, the authors’ RNA-seq analysis of the brush cells indicates the presence of the machinery required to produce LTs.

Our focus is often drawn toward the most prevalent cell types with the expectation that these cells are the most important mediators of an inflammatory response or disease. Studies such as that by Bankova et al. reveal that rare cell populations might in fact be the most important and “tuftest” targets for future therapeutic interventions.

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