biostudies-literatureTrier AMNEI NIH HHSNIDDK NIH HHSDoris Duke Charitable FoundationNIAID NIH HHSNHLBI NIH HHSNIAAA NIH HHSNCI NIH HHSNINDS NIH HHSNational Institutes of HealthNIAMS NIH HHS1473-1480.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC8934751biostudies-literatureUnknown149(4)<h4>Background</h4>Chronic pruritus, or itch, is common and debilitating, but the neuroimmune 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.<h4>Objectives</h4>We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models.<h4>Methods</h4>Plasma 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.<h4>Results</h4>IL-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.<h4>Conclusions</h4>These 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 into future therapeutic strategies targeting the IL-33 pathway for chronic itch.The Journal of allergy and clinical immunologyIL-33 signaling in sensory neurons promotes dry skin itch.PMC8934751R01 AR077183F30 AI154912R01 HL152245T32 HL007317R01 EY024704R21 AI167047P30 DK052574R01 NS111719R01 AA027065P30 CA091842RF1 NS113881K08 AR065577T32 AI007163R01 NS042595R01 DK103901R01 AI1257432016104R01 AR077007R01 AI163146R01 AR070116Avraham OOetjen LKMack MRJoshita SFord ZKDavidson SLiu QAlexander-Brett JTrier AMGuo CJDehner CTamari MZhao YCoble DVer Heul AMBadic ACavalli VFredman AFeng JHu HKim BSGereau RWKubo MfalseIL-33 signaling in sensory neurons promotes dry skin itch.<h4>Background</h4>Chronic pruritus, or itch, is common and debilitating, but the neuroimmune 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.<h4>Objectives</h4>We sought to determine if IL-33 signaling in sensory neurons is critical for the development of chronic itch in 2 divergent pruritic disease models.<h4>Methods</h4>Plasma 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.<h4>Results</h4>IL-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.<h4>Conclusions</h4>These 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 into future therapeutic strategies targeting the IL-33 pathway for chronic itch.2022-01-01T00:00:00Z2022 Apr2026-05-09T23:43:16.822Z2025-04-04T22:13:18.571ZS-EPMC89347513456010410.1016/j.jaci.2021.09.014