IL-33 Signaling in Sensory Neurons Promotes Dry Skin Itch.

Abstract

BACKGROUND\nChronic pruritus, or itch, is common and debilitating, but the neuro-immune mechanisms that drive chronic itch are only starting to be elucidated. Recent studies demonstrate that the IL-33 receptor (IL-33R) is expressed by sensory neurons. However, whether sensory neuron-restricted activity of IL-33 is necessary for chronic itch remains poorly understood.\n\n\nOBJECTIVES\nWe sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in two divergent pruritic disease models.\n\n\nMETHODS\nPlasma levels of IL-33 were assessed in patients with atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO). Mice were generated to conditionally delete IL-33R from sensory neurons. The contribution of neuronal IL-33R signaling to chronic itch development was tested in mouse models that recapitulate key pathologic features of AD and CPUO, respectively.\n\n\nRESULTS\nIL-33 was elevated in both AD and CPUO as well as their respective mouse models. While neuron-restricted IL-33R signaling was dispensable for itch in AD-like disease, it was required for the development of dry skin itch in a mouse model that mirrors key aspects of CPUO pathology.\n\n\nCONCLUSION\nThese data highlight how IL-33 may be a predominant mediator of itch in certain contexts, depending on the tissue microenvironment. Further, this study provides insight for future therapeutic strategies targeting the IL-33 pathway for chronic itch.