Ualiyeva, S. | bioRxiv Science

bioRxiv2022

Olfactory microvillar tuft cells direct neurogenesis during allergic inflammation

The olfactory neuroepithelium serves as a sensory organ for odors and is part of the nasal mucosal barrier. Olfactory sensory neurons are surrounded and supported by epithelial cells. A subset of these, microvillous cells (MVCs), are strategically positioned at the apical surface but their specific functions are still enigmatic and their relationship to the rest of the solitary chemosensory cell family is unclear. Here, we establish that the larger family of MVCs comprises tuft cells and ionocytes in both mice and humans. Olfactory TRPM5+ tuft-MVCs share a core transcriptional profile with the chemosensory tuft family, prominently including the machinery for lipid mediator generation. Integrating analysis of the respiratory and olfactory epithelium, we define the unique receptor expression of TRPM5+ tuft-MVC compared to the G[a]-gustducin+ respiratory tuft cells and characterize a new population of glandular DCLK1+ tuft cells. To establish how allergen sensing by tuft-MVCs might direct olfactory mucosal responses, we employed an integrated single-cell transcriptional and protein analysis. We defined a remodeling olfactory epithelial switch pathway with induction of Chil4 and a distinct pathway of proliferation of the quiescent olfactory horizontal basal stem cell (HBC), both triggered in the absence of significant olfactory apoptosis. While the Chil4 pathway was dependent on STAT6 signaling and innate lymphocytes, neither were required for HBC proliferation. HBC proliferation was dependent on tuft-MVCs, establishing these specialized epithelial cells as both sensors for allergens and regulators of olfactory stem cell responses. Together our data provide high resolution characterization of the nasal tuft cell heterogeneity and uncover a novel mechanism by which TRPM5+ tuft cells direct the olfactory mucosal response to allergens. One Sentence SummaryWe identify the enigmatic TRPM5+ olfactory microvillous cells as tuft cells, and show their functional role as regulators of olfactory stem cell proliferation in response to environmental signals.

immunology↗

bioRxiv2021

Tuft cell-produced cysteinyl leukotrienes and IL-25 synergistically drivelung type 2 inflammation

Aeroallergen sensing by airway epithelial cells can trigger pathogenic immune responses leading to chronic type 2 inflammation, the hallmark of airway diseases such as asthma. Airway tuft cells are specialized chemosensory epithelial cells and the dominant source of the epithelial cytokine IL-25 in the trachea and of cysteinyl leukotrienes (CysLTs) in the naive murine nasal mucosa. The interaction of IL-25 and CysLTs and the contribution of tuft cell-derived CysLTs to the development of allergen-triggered inflammation in the airways has not been clarified. Here we show that inhalation of LTC4 in combination with a subthreshold dose of IL-25 leads to dramatic synergistic induction of type 2 inflammation throughout the lungs, causing rapid eosinophilia, dendritic cell (DC) and inflammatory type 2 innate lymphoid cell (ILC2) expansion, and goblet cell metaplasia. While lung eosinophilia is dominantly mediated through the classical CysLT receptor CysLT1R, type 2 cytokines and activation of innate immune cells require signaling through both CysLT1R and CysLT2R. Tuft cell-specific deletion of the terminal enzyme requisite for CysLT production, Ltc4s, was sufficient to reduce both the innate immune response in the lung - eosinophilia, KLRG1+ ILC2 activation and DC recruitment - and the systemic immune response in the draining lymph nodes after inhalation of the mold aeroallergen Alternaria. Our findings identify surprisingly potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs. One Sentence SummaryTuft cells produce two highly synergistic mediators: LTC4 and IL-25 to cooperatively induce allergen-driven airway inflammation.

immunology↗