A mouse neuroimmune circuit that regulates allergic inflammation in the esophagus

Eosinophilic esophagitis (EoE) is a chronic, allergic disease associated with refractory pain in patients, yet the function of the nervous system in EoE pathogenesis remains ill-defined. Here we elucidate a mouse neuroimmune circuit that is linked to type 2-associated allergic inflammation and clinical responses in the esophagus, including pain. In a mouse allergy model, allergen exposure evokes pain-like behavior, increases esophageal Nav1.8+ sensory innervation density, and alters nociceptor sensitization. Thoracic dorsal root ganglia (DRG) show expression of type 2 cytokine receptors Il4ra and Il13ra1, and IL-4 and IL-13 sensitize DRG neurons to noxious agents. Mechanistically, conditional deletion of Il4ra in mouse NaV1.8+ neurons attenuate the above allergen-induced phenotypes as well as the levels of insulin-like growth factor 1 (IGF-1); in parallel, IGF-1 receptor inhibition also dampens these disease features. Finally, EoE patient samples show increased esophageal neuronal density when compared with controls. Our findings thus describe a type 2 neuroimmune circuit that potentially contributes to EoE pathogenesis, including pain. The allergic disease eosinophilic esophagitis (EoE) is often accompanied by refractory pain, but how neuroimmune crosstalk impacts EoE remains unclear. Here, the authors show, using mouse models of allergic inflammation, that allergen exposure increases esophageal innervation and alters sensitivity of sensory neurons, identifying a potential feedforward loop for amplifying inflammation and causing pain.