Neuroimmune interactions regulate development of allergic inflammation

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PROJECT SUMMARY Asthma is a highly prevalent inflammatory disorder of the airways that can lead to severe bronchoconstriction and respiratory failure. Aberrant type 2 immune responses to allergens have long been appreciated as the major driver of asthma. However, about 10% of patients have severe, persistent difficult to control asthma, marked by the production of interleukin (IL)-17. This leads to neutrophilic airway inflammation, either alone or in conjunction with type 2 inflammation, which responds poorly to current therapies, including corticosteroids. These observations highlight the importance of identifying molecular targets capable of regulating both type 2 and type 17 responses in allergic lung inflammation. Innate lymphoid cells (ILCs), a recently described cell type, have been shown to play a critical role in the initiation and amplification of mucosal tissue inflammation. ILC2s rapidly produce pro-inflammatory cytokines like IL-5 and IL-13, which mediate eosinophil recruitment and goblet cell hyperplasia, in response to epithelial alarmins like IL-25 and IL-33. ILC3s, on the other hand, produce IL-17, and promote and propagate development of neutrophilic asthma. However, the molecular mechanisms that promote pro-inflammatory phenotypes in ILC2s and ILC3s remain poorly understood, particularly in the context of allergic airway inflammation, We recently undertook massively parallel droplet-based single-cell RNA-sequencing to develop a transcriptional atlas of lung resident ILCs under homeostatic and inflammatory conditions and identify novel regulators of ILC function. We found that receptors for two different neuropeptides, neuromedin U (NMU) and calcitonin gene related peptide (CGRP), were expressed on lung ILCs. Our data shows that NMU directly activates ILCs in the presence of the alarmin IL-25 to acquire a pro-inflammatory phenotype. In contrast, the neuropeptide CGRP inhibits ILC2 production of pro-inflammatory cytokines after stimulation with the alarmin IL-33. These data lead us to hypothesize that following allergen challenge, neuronal signals via neuropeptide receptors can potently modulate the ILC-mediated allergic inflammation. We propose three different aims to address this hypothesis: 1) Identify and validate novel regulators of ILC function via single-cell transcriptional analysis of in vivo-derived ILC2s and ILC3s; 2) Determine the mechanism(s) by which NMU/NMUR1 signaling converts homeostatic ILCs into pro-inflammatory ILCs; 3) Study the mechanism by which the neuropeptide CGRP regulates ILC2 function and development of allergic lung inflammation. Together, these three aims will create a highly integrated transcriptional map of innate lymphoid cells (ILC2s and ILC3s) during allergen exposure, and elucidate how the nervous system may regulate development of allergic airway inflammation by activating neuropeptide receptors on ILCs. !