Abstract

Chronic itch is associated with a broad range of medical conditions, from inflammatory skin diseases to cancer and organ dysfunction, and has a lifetime prevalence of up to 20%. Despite being common and debilitating, the cellular and molecular mechanisms that drive chronic itch are just beginning to be elucidated. Thus, therapeutic options are limited. Recent studies have identified that various pro-inflammatory cytokines can directly activate sensory neurons. This has resulted in mounting interest in the therapeutic potential of inhibiting these neuro-immune interactions. IL-33 is constitutively expressed by epithelial cells, which allows for its rapid release upon tissue damage or stress. Recent studies indicate that IL-33 is important for the development of chronic itch, however, the precise mechanisms by which IL-33 mediates itch remain largely unexplored. IL-33 is a key upstream promoter of type 2 inflammation, and a wide variety of immune cells express its receptor ST2 (IL-33R). Strikingly, IL-33R is also expressed by sensory neurons. Thus, we sought to determine if IL-33R signaling specifically in sensory neurons is necessary for the development of chronic itch in preclinical mouse models of chronic itch. We found that IL-33 is elevated in two different chronic itch conditions in humans, atopic dermatitis (AD) and chronic pruritus of unknown origin (CPUO), as well as their respective mouse models. To evaluate the potential role of neuronal IL-33R in itch, we generated novel mice where IL-33R is conditionally deleted in sensory neurons. Interestingly, sensory neuron-restricted IL-33R signaling was dispensable for itch development in the inflammatory AD-like setting in mice. Instead, neuron-expressed IL-33R was critically required for the development of chronic itch in a mouse model that recapitulates key pathologic features of CPUO. Thus, our findings demonstrate that while the IL-33-IL-33R axis is a known pro-inflammatory axis in AD, it is dispensable at the neuro-immune interface for itch. Rather, neuronal IL-33R emerges as a key regulator of pruriceptor function in the less inflammatory condition CPUO. These findings shed light on the context-dependent nature of IL-33 in driving pathologies like itch as well as current and future trials of anti-IL-33 monoclonal antibody therapies.

Committee Chair

Brian Kim

Committee Members

Erik Musiek; Gwen Randolph; Hongzhen Hu; Jennifer Alexander-Brett; Steve Van Dyken

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Immunology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

5-6-2025

Language

English (en)

Author's ORCID

https://orcid.org/0000-0003-3156-6755

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