2. Academic Validation
  3. Multiomics reveals CCL3-driving neuronal sensitization in chronic pruritus of unknown origin

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

  • J Invest Dermatol. 2025 Nov 29:S0022-202X(25)03613-9. doi: 10.1016/j.jid.2025.10.620.
Lu Zhang 1,  Lerong Lun 1,  Maoqia Shen 2,  Wanying Zhai 1,  Jui-Wen Chang 3,  Wenjing Jiang 1,  Xiru Tang 1,  Wenhui Liu 1,  Yali Gao 1,  Huilin Su 1,  Jiande Han 1,  Fengxian Li 4,  Fang Wang 5
Affiliations

Affiliations

  • 1 Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Department of Anesthesiology, Institute of Perioperative Medicine and Organ Protection, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
  • 3 Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, China.
  • 4 Department of Anesthesiology, Institute of Perioperative Medicine and Organ Protection, Zhujiang Hospital, Southern Medical University, Guangzhou, China. Electronic address: [email protected].
  • 5 Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, China. Electronic address: [email protected].
PMID: 41320115 DOI: 10.1016/j.jid.2025.10.620
Abstract

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.

Keywords

CCL3; CCR1; Chronic pruritus; Monocytes; Neuronal sensitization.

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