Multiomics reveals CCL3-driving neuronal sensitization in chronic pruritus of unknown origin

Chronic pruritus of unknown origin is a debilitating condition characterized by persistent itch without an identifiable cause, yet its underlying mechanisms remain elusive. Using single-cell RNA sequencing, we identified systemic immune dysregulation in patients with chronic pruritus of unknown origin, characterized by upregulated CCL3 expression in monocytes and NK cells. Plasma CCL3 levels effectively distinguished patients with chronic pruritus of unknown origin from healthy controls and strongly correlated with itch severity. Although CCL3 did not function as a direct pruritogen in mice, it enhanced sensory neuron sensitivity through CCR1, thereby amplifying scratching responses to diverse pruritogens. Furthermore, cutaneous CCL3 was markedly upregulated in a chronic dry-skin itch model. Inhibition of CCR1 or neutralization of CCL3 significantly suppressed scratching behavior in this model. Together, these findings identify CCL3 as a potential diagnostic biomarker for chronic pruritus of unknown origin and highlight the CCL3-CCR1 axis as a critical neuroimmune pathway underlying chronic itch. This CCL3-CCR1 signaling pathway may represent a promising therapeutic target for refractory pruritic disorders.