Elevated Eosinophil Lineage-Committed Progenitors In Skin Lesions Of Patients With Moderate-To-Severe Atopic Dermatitis

Abstract

RATIONALE: Atopic dermatitis (AD) is a chronic inflammatory skin disorder with itch as its most debilitating symptom. Blockade of the type 2 cytokines IL-4 and IL-13 with dupilumab, an anti-IL-4Ra antibody, has demonstrated unprecedented efficacy in treating AD including rapid improvements of itch. However, how disrupting type 2 cytokine signaling improves itch remains unknown. Given the remarkable effects of IL-4Ra blockade on itch, we hypothesized that, in addition to their known proinflammatory functions, IL-4 and IL-13 directly stimulate sensory neurons to mediate chronic itch. METHODS: We investigated the contributions of neuronal IL-4 and IL-13 signaling to chronic itch using sensory neuron-specific genetic deletion of type 2 cytokine signaling components and pharmacologic blockade with JAK inhibitors in a mouse model of AD. We also performed observational studies to explore the anti-itch properties of JAK inhibitors in patients. RESULTS: We found that IL-4 and IL-13 directly activate itch-sensory neurons in mice. Strikingly, we observed that IL-4 also activates human sensory neurons, suggesting that neuronal type 2 cytokine signaling promotes itch across species. Using conditional deletion of IL-4Ra from sensory neurons, we discovered that neuronal IL-4Ra critically mediates AD-associated itch. Additionally, we found that type 2 cytokine responses in neurons were dependent on JAK1, and disruption of neuronal JAK1 signaling reduced chronic itch. Finally, in translational studies, we found that JAK inhibitors markedly improved itch symptoms in chronic itch patients. CONCLUSIONS: The classical immune signaling molecules IL-4Ra and JAK1 represent new targets within the sensory nervous system to treat itch in AD and other chronic itch disorders.