Type 2 cytokines act on enteric sensory neurons to promote parasitic host defense 9411

Abstract Description Despite the profound influence neuronal mediators have on immune cells, our understanding of how inflammation influences enteric neuron function remains incomplete. We reanalyzed multiple single-cell RNA-sequencing datasets of enteric neurons and discovered a subset of enteric sensory neurons with high expression of Il13ra1 and Il4ra—which encode a receptor for the hallmark type 2 cytokines IL-4 and IL-13. This enteric sensory neuron subset co-expresses the genes for neuromedin U (NMU) and calcitonin gene-related peptide beta (CGRPβ), two neuropeptides we have previously shown to directly amplify or inhibit, respectively, type 2 cytokine responses in immune cells. Enteric neuron-specific Il13ra1 conditional knockout (cKO) mice failed to control intestinal worm burden and fecundity after infection with the helminth parasite Heligmosomoides Polygyrus (Hp). Furthermore, Hp-infected Il13ra1 cKO mice displayed severe impairments in duodenal Nmu and Calcb expression, suggesting neuronal IL-4/IL-13-receptor signaling contributes to neuropeptide up-regulation during helminth infection. In vitro enteric neuron cultures treated with IL-13 or IL-4 displayed up-regulation of Nmu and Calcb, indicating that type 2 cytokines are sufficient to induce select neuropeptide expression in enteric neurons. All together, these data significantly improve our understanding of the cytokine-neuropeptide feedback loops between immune cells and enteric neurons during type 2 inflammation. Funding Sources Food Allergy Science Initiative (FASI) 2021-NEURO-218978113 (VKK) National Institutes of Health grant RO1AI 39536 (VKK) National Institutes of Health grant RC2 DK114784 (RJX) Department of Defense Discovery Award PR170625 (MR) National Institutes of Health grant DK135707 (MR) National Science Foundation Graduate Research Fellowship Program (RMB) National Institutes of Health T32 training grant (RMB) Topic Categories Neuroimmunology (NEUR)