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Description

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This seminar will feature two talks on the mechanisms of itch, including:

Peripheral Sensitization in Chronic Pruritus (Pang-Yen Tseng)
Chronic itch is a major symptom of many inflammatory skin diseases. This type of pruritus is thought to be facilitated by cytokines that activate cutaneous nerve fibers, however, the molecular components and mechanisms involved are poorly understood. We found that itch-selective sensory neurons highly express the oncostatin M (OSM) receptor (OSMR). By analyzing RNA sequencing data from human skin biopsies, we found that OSM is commonly upregulated in psoriasis, atopic dermatitis, and cutaneous T-cell lymphoma, which are all diseases associated with chronic itch. Single-cell sequencing analysis showed that OSM is mainly produced by cutaneous T cells. Unlike canonical pruritogens such as histamine or chloroquine, OSM sensitizes neurons by potentiating neural responses to pruritogens and by enhancing neural excitability, leading to exaggerated itch. Sensory neuron-specific OSMR knockout greatly mitigated the itch phenotype and skin inflammation in a psoriasiform dermatitis mouse model. Pharmacologically, antagonizing the OSMR complex effectively alleviated inflammatory skin pruritus. Together our results reveal OSM as a novel itch neuromodulator and suggest that antagonizing OSM signal transduction could be a novel antipruritic strategy.


A Basophil-Neuronal Axis Promotes Itch (Fang Wang)
Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disorder associated with severe itch. In addition to chronic itch, patients often experience intense acute itch exacerbations. Recent seminal discoveries have unearthed the neuroimmune circuitry of itch, leading to the development of novel treatments. However, mechanisms underlying acute itch exacerbations remain overlooked. Moreover, although IgE reactivity to various allergens is a well-known feature of AD, its precise role in AD pathogenesis remains unclear. By reviewing a large cohort of patients with moderate-to-severe AD in clinical trials, we found that patients harboring allergen-specific IgE are prone to develop acute itch flares. Further, to explore the role of IgE in AD-related itch, we employed a murine model in which allergen-specific IgE was generated in the setting of AD-like disease to evoke allergen-induced acute itch flares. Classically, the mast cell-histamine axis has been recognized as the canonical itch paradigm triggered by IgE. Strikingly, although IgE-mediated acute itch was dependent on the mast cell-histamine axis in steady-state, in the setting of AD-like inflammation, mast cells and histamine were dispensable. Instead, we demonstrate that chemogenetic activation of circulating basophils was sufficient to evoke acute itch behavior in animals. Further, we found that acute itch flares were alleviated by basophil depletion and interruption of leukotriene C4 signaling in AD-like inflammation. Collectively, these findings reveal a previously unrecognized contribution of the IgE-basophil-leukotriene pathway in mediating acute itch, which may explain why mast cell- and histamine-targeted therapies have demonstrated poor anti-itch efficacy in AD.