Dissecting an IL4RA-dependent neuroimmune circuit in eosinophilic esophagitis

The National Institute of Allergy and Infectious Diseases awarded Cincinnati Children's Hospital Medical Center $170,492 on February 14, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to support basic research dissecting an IL4RA-dependent neuroimmune circuit in eosinophilic esophagitis.

The research investigates the role of the peripheral nervous system in eosinophilic esophagitis (EOE) pathogenesis, specifically how sensory neurons sense IL-4 and IL-13 cytokines and activate to produce insulin-like growth factor 1 (IGF-1), which modulates immune cell function and regulates neuronal sensitization and pain. Preliminary data demonstrates that mice with experimental EOE display elevated eosinophil levels, increased non-evoked pain, heightened sensory neuron innervation density in the esophagus, and altered sensitivity of sensory neurons to noxious stimuli. The research aims to address the disconnect between eosinophil levels and persistent symptoms in patients in histological remission, indicating that EOE pathogenesis involves mechanisms beyond eosinophilic inflammation alone.

Performance occurs in Cincinnati, Ohio, with a completion date of August 16, 2029. This is a Project Grant, the standard NIH research grant mechanism supporting individual investigator-initiated studies. The award falls under NIAID's competitive research grant program supporting biomedical research and research training in infectious diseases and allergic conditions.

Abstract

Eosinophilic esophagitis is a chronic food antigen-driven allergic inflammatory disease associated with symptoms such as refractory pain. While esophageal eosinophilia is a hallmark of the disease, there is often a disconnect between eosinophil levels and quality of life, as patients in histological remission often have persistent symptoms. Thus, the mechanism of symptom development in EOE is likely more complex than eosinophilic inflammation alone. Recent studies demonstrate that the function of afferent nerves extends beyond their role of relaying nociceptive information back to the CNS. Sensory neurons can directly sense IL-4 and IL-13, two influential cytokines in EOE pathogenesis. These have been shown to activate nerves to produce factors that then modulate immune cell function. One such factor is insulin-like growth factor 1 (IGF-1), which can regulate neuronal sensitization and pain. In allergic inflammation and asthma, IGF-1 has been shown to promote mast cell survival, regulate eosinophil levels, and cause proliferation of epithelial cells. Taken together, evidence is emerging that the peripheral nervous system may contribute to allergic disease pathophysiology as an intricate part of the innate immune response. But the role of the nervous system in EOE pathogenesis has not received much attention. Preliminary data demonstrated that mice with experimental EOE display elevated eosinophil levels, increased non-evoked pain, heightened sensory neuron innervation density in the esophagus, and altered sensitivity of sensory neurons to noxious stimuli. Sensory neuron-specific deletion of IL4RA (IL4RA-/-NAV1.8) reduced inflammatory gene expression, histological severity, eosinophil levels, and innervation density in allergic animals compared to their wild-type counterparts. Additionally, the cell bodies of esophageal afferents in the dorsal root ganglia (drgs) in mice with experimental EOE express elevated IGF-1, but is significantly reduced in allergic IL4RA-/-NAV1.8 mice drgs and esophagi. Mechanistically, IGF-1 levels have been linked to IL4RA activation in multiple cell types. Therefore, we will test the central hypothesis that the activation of esophageal sensory neurons via IL4RA during allergic inflammation drives increased nerve hypersensitivity and subsequent inflammation via IGF-1 signaling. Transgenic, dreadd, and AAV technology will be used to determine the role of sensory neurons on nociception and inflammation in experimental EOE. Pain-related behavioral assays, in vivo calcium imaging of drgs, and molecular analyses (qpcr, flow cytometry, IHC, if) of the esophagus will be conducted. Aim 1 will elucidate the role of peripheral nociceptive neurons and their expression of IL4RA in a murine model of EOE through chemogenetic manipulation of esophageal neuron firing. Aim 2 will determine whether sensory-neuron derived IGF-1 is necessary to increase esophageal hypersensitivity and inflammation in experimental EOE. This research will be the first to assess the presence of a potential neuroimmune mechanism by which nerves contribute to disease development and symptom severity via expression of IL4RA and IGF-1 signaling, in EOE.