Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 149, Issue 4, Pages 1473-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2021.09.014
Keywords
Atopic dermatitis; chronic pruritus of unknown origin; dry skin; IL-33; itch; neuroimmunology; pruriceptor; pruritogen
Categories
Funding
- Celgene Corporation
- Doris Duke Charitable Foundation
- LEO Pharma
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [K08AR065577, R01AR070116, R01AR077007, R21AI167047]
- National Institute of Allergy and Infectious Diseases (NIAID) [T32AI007163]
- National Heart, Lung, and Blood Institute (NHLBI) [T32HL007317]
- NIAID [R01AI125743, F30AI154912]
- National Institute of Neurological Disorders and Strokes (NINDS) [R01NS042595]
- NHLBI [R01HL152245]
- Burroughs Welcome Fund [1014685]
- McDonnell Center for Cellular and Molecular Neurobiology
- NINDS [RF1NS113881, R01NS111719]
- National Institute for Alcohol Abuse and Alcoholism (NIAAA) [R01AA027065]
- NIAMS [R01AR077183]
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [R01DK103901]
- Washington University School of Medicine Digestive Disease Research Core Center (NIDDK) [P30DK052574]
- Brain Research Foundation Fay/Frank Seed Grant
- Pew Scholar Award
- National Cancer Institute [P30CA091842]
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IL-33 signaling may play a critical role in the development of chronic itch, depending on the tissue microenvironment.
Background: 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. Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.
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