Jorge (Jay) Ortiz-Carpena  (Mentor: Debroski Herbert, PhD)

"Neuron-dependent tuft cell expansion controls allergic Type 2 inflammation in the sinonasal tract"

Jorge F. Ortiz-Carpena, Christopher Pastore, Li-Yin Hung, Michael A. Kohanski, Andrew E. Vaughan, Noam A. Cohen, and De’Broski R. Herbert

Sinonasal Type 2 inflammation underlies the pathophysiology of allergic rhinitis, a chronic disease affecting >300 million people worldwide. Whether neuro-immune interactions in the sinonasal mucosa drive diseases such as allergic fungal rhinosinusitis (AFRS) remains unknown. Sensory neurons are closely apposed to sinonasal tuft cells (STC), which are a rare lineage of epithelial cells that initiate inflammation by secreting pro-Type 2 cytokines. Neurons innervating STC express the transient receptor potential vanilloid 1 (TRPV1+) ion channel, implying that STC function(s) may be influenced by neuronal inputs. In this study, we established a mouse model of sinonasal Type 2 allergic inflammation evoked by administration of Alternaria alternata and Aspergillus fumigatus-fungal allergen mix (FAM). This model results in the expansion of STC, tissue ILC2, eosinophils, goblet cells, and increased levels of IL-25 and IL-33 in the sinonasal fluid. Importantly, local ablation of sinonasal TRPV1+ sensory neurons significantly inhibits FAM-induced bouts of sneezing, STC expansion, and eosinophil recruitment. The central hypothesis is that TRPV1+ sensory neurons produce factors that cause STC to release Type 2 cytokines and drive allergic disease pathophysiology. Ongoing studies are designed to (1) determine whether sinonasal TRPV1+ sensory neurons are essential and/or sufficient to initiate Type 2 allergic responses and excessive sneezing in a STC-dependent manner and (2) identify the mediator(s) released by TRPV1+ sensory neurons that induce STC expansion and/or cytokine release. This project stands to reveal important insight into the mechanisms wherein sensory neuron-STC interactions can promote allergic inflammation and may offer new avenues for therapeutic intervention in human disease.