Immune dysregulation and CCL3-induced neuronal sensitization underlie chronic pruritus of unknown origin
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Presented at: Society for Investigative Dermatology 2025
Date: 2025-05-07 00:00:00
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Summary: Chronic pruritus of unknown origin (CPUO) is a debilitating condition that significantly affects quality of life, yet the underlying mechanisms remain poorly understood. Single-cell sequencing and Luminex multiplex protein analysis of patient samples were used to unravel the immune landscape of CPUO, with subsequent mechanistic validation by mouse itch behavioral assays, immunofluorescence, and calcium imaging. We showed that CPUO patients (n = 35) manifested a wide age range without notable elevation in IgE or eosinophil levels. Furthermore, single-cell transcriptional analysis revealed distinct immune cell function and interactions in CPUO compared to controls. Circulating classical monocytes were significantly reduced in CPUO patients but exhibited enhanced tissue migration, chemotaxis, and antigen presentation capabilities. Natural killer (NK) and T cells displayed increased proportions and prominent senescence signatures compared to controls, with NK cells showing mitochondrial dysfunction and enhanced stress responses. Analysis of the T cells highlighted a notable shift towards T helper 2 predominance and reduced regulatory T cells. Consistently, plasma protein profiling identified several elevated inflammatory mediators in CPUO patients compared to HCs. Among these, CCL3 showed robust upregulation and contributes to pruritus through CCR1-dependent sensitization of pruriceptive neurons. In conclusion, our characterization of CPUO as a distinct entity driven by systemic immune dysregulation and CCL3-mediated neuronal sensitization provides mechanistic insights into its pathophysiology and opens new avenues for therapeutic intervention. Lu Zhang<sup>1</sup>, Lerong Lun<sup>1</sup>, Fang Wang<sup>2, 1</sup> 1. Department of Dermatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China. 2. Guangdong Provincial Dermatology Hospital, Guangzhou, Guangdong, China. Translational Studies: Cell and Molecular Biology