Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2, 2020, Ualiyeva et al

Andy · Feb 10, 2020

Nasal sensors of danger
The epithelium of the nasal mucosa includes specialized chemosensory cells in the brush/tuft cell family that use taste receptors to detect environmental stimuli. Activated brush cells initiate host protective responses by releasing mediators including the neurotransmitter acetylcholine and the cytokine IL-25. Ualiyeva et al. detected two subsets of nasal brush cells in mice and used RNA sequencing and functional assays to identify additional brush cell effector mechanisms. Brush cells were identified as the primary source of the proinflammatory cysteinyl leukotrienes LTC4, LTD4, and LTE4 in naïve nasal mucosa, a response that depends on the P2Y2 purinergic receptor responding to ATP as a danger signal. These findings provide new insights into how brush cells contribute to both physiologic and pathologic mucosal inflammation including respiratory allergy symptoms.

Abstract
Chemosensory epithelial cells (EpCs) are specialized cells that promote innate type 2 immunity and protective neurally mediated reflexes in the airway. Their effector programs and modes of activation are not fully understood. Here, we define the transcriptional signature of two choline acetyltransferase–expressing nasal EpC populations. They are found in the respiratory and olfactory mucosa and express key chemosensory cell genes including the transcription factor Pou2f3, the cation channel Trpm5, and the cytokine Il25.

Moreover, these cells share a core transcriptional signature with chemosensory cells from intestine, trachea and thymus, and cluster with tracheal brush cells (BrCs) independently from other respiratory EpCs, indicating that they are part of the brush/tuft cell family. Both nasal BrC subsets express high levels of transcripts encoding cysteinyl leukotriene (CysLT) biosynthetic enzymes.

In response to ionophore, unfractionated nasal BrCs generate CysLTs at levels exceeding that of the adjacent hematopoietic cells isolated from naïve mucosa. Among activating receptors, BrCs express the purinergic receptor P2Y2. Accordingly, the epithelial stress signal ATP and aeroallergens that elicit ATP release trigger BrC CysLT generation, which is mediated by the P2Y2 receptor. ATP- and aeroallergen-elicited CysLT generation in the nasal lavage is reduced in mice lacking Pou2f3, a requisite transcription factor for BrC development. Last, aeroallergen-induced airway eosinophilia is reduced in BrC-deficient mice.

These results identify a previously undescribed BrC sensor and effector pathway leading to generation of lipid mediators in response to luminal signals. Further, they suggest that BrC sensing of local damage may provide an important sentinel immune function.
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Paywall, https://immunology.sciencemag.org/content/5/43/eaax7224
Sci hub, https://sci-hub.se/10.1126/sciimmunol.aax7224

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Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2, 2020, Ualiyeva et al

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Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2, 2020, Ualiyeva et al

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