Jay Ortiz-Carpena

"Sinonasal Tuft Cells and Sensory Neuron interactions regulate Type 2 allergic inflammation"
Jorge F. Ortiz-Carpena, Christopher Pastore, Li-Yin Hung, Michael A. Kohanski, Andrew E. Vaughan, Noam A. Cohen, and De’Broski R. Herbert
Sinonasal Tuft Cells (STC) are a rare lineage of sinonasal epithelial cells implicated in Type 2 allergic airway diseases such as allergic fungal rhinosinusitis (AFRS). Through yet unknown mechanisms, STC numerically expand and release cytokines such as interleukin-25 (IL-25) and inflammatory eicosanoids including cysteinyl leukotrienes (CysLT). IL-25 and CysLT cooperatively induce ILC2 activity and the pathophysiological features of AFRS (e.g. eosinophil expansion and goblet cell metaplasia). STC are innervated by sensory neurons of the trigeminal ganglion (TG), although it is not clear whether interactions between STC and neurons in the airways can initiate or augment the rapid sensing of allergen-induced Type 2 inflammation. In this study, we established a mouse model of eosinophilic inflammation evoked by intranasal (i.n.) administration of Alternaria alternata and Aspergillus fumigatus-fungal allergen mix (FAM) over the course of 3 weeks in C57BL/6J mice. Results indicate that FAM induced a numerical expansion of STC, sinonasal tissue eosinophils, ILC2, and increased levels of IL-25 and CysLT in the sinonasal fluid. In addition, immunofluorescence imaging revealed that STC were in close vicinity of NaV1.7+ TG sensory neurons in the respiratory epithelium of allergen exposed vs. PBS control mice. Ongoing studies are designed to test for mucus accumulation and pulmonary hyperresponsiveness following methacholine challenge. Taken together, this model offers the ability to study the mechanisms of sinonasal immunity to fungal allergens, as well as the contributions of microbiota to STC-sensory neuron interactions within the sinonasal tract. A STC-sensory neuron circuit has not been established in this anatomic region, thus implicating these two cell types in allergic disease may offer new avenues for therapeutic intervention in the context of human disease.