Identification of a Neuroimmune Circuit that Regulates Allergic Inflammation in the Esophagus

Abstract

Eosinophilic esophagitis is a chronic food antigen-driven allergic inflammatory disease associated with symptoms involving the nervous system such as refractory pain. Yet, the role of the nervous system in disease pathogenesis has not received much attention. Herein, we demonstrate that allergen exposure evokes pain-like behavior in association with increased nociceptor signaling and transcriptional responses in dorsal root ganglia. NaV1.8+ sensory nerves were found traveling along the length of the esophagus, organized in distinct bundles adjacent to the basal epithelium, with beta III-tubulin+ sensory nerves distributed more distal to the lumen. Targeted deletion of Il4ra in NaV1.8+ neurons impeded allergen-induced increases in nerve innervation density. Furthermore, Il4ra-/-NaV1.8 mice had diminished allergen-induced allergic inflammation in the esophagus including eosinophilia and transcription of pro-inflammatory genes. Translational studies revealed extensive myelinated nerve innervation in the human esophagus, which was increased in patients with eosinophilic esophagitis. Taken together, these data indicate that allergic inflammation is associated with an increase in non-evoked pain, esophageal nerve density, altered sensitivity of sensory neurons, and transcriptional changes in dorsal root ganglia. These finding identify a type 2 neuroimmune circuit that involves the interplay of allergen-induced IL-4 receptor-dependent DRG responses that modify esophageal end-organ inflammatory responses.