Wei Ge1,2 · Yu Feng3  · Li Zhang4  · Qian‑Liang Wang1  · Cheng‑Wei Zhang5  · Zhi‑Hong Wang6  · Guo‑Kun Zhou7  · Shi‑Yu Sun7  · Xiu‑Hua Miao8  · Tong Liu7  · Bin Wu9  · Jun Yan1

1 Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China 

2 Department of Orthopedics, Yancheng First People’s Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng 224000, China 

3 Department of Rheumatology and Immunology, The Fourth Affiliated Hospital of Soochow University, Suzhou 215000, China 

4 Department of Anesthesiology, The First People’s Hospital of Kunshan Affiliated with Jiangsu University, Kunshan 215300, China 

5 Department of Thoracic Surgery, Capital Medical University, Electric Power Teaching Hospital, Beijing 100073, China 

6 Cambridge‑Suda Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou 215000, China 

7 Institute of Pain Medicine and Special Environmental Medicine, Nantong University, Nantong 226001, China 

8 Department of Pain Management, Affiliated Hospital and Medical School of Nantong University, Nantong 226001, China 

9 Department of Anesthesiology and Pain Rehabilitation, Cardiopulmonary and Critical Care Rehabilitation Center, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai 200092, China

Abstract

Endoplasmic reticulum (ER) stress plays a significant role in chronic pain, but its potential involvement in chronic itch remains largely unexplored and poorly understood. In the current study, we investigated whether ER stress signaling in keratinocytes contributes to the pathogenesis of chronic itch. Our behavioral tests showed that the ER stress inhibitor 4-PBA attenuated itch-related behaviors in both acute and chronic itching mouse models, and reduced compound 48/80 and serotonin-induced activity of dorsal root ganglion (DRG) neurons. qPCR and western blotting revealed that the ER stress-related proteins and Lipocalin-2 (LCN2) were significantly elevated in the affected skin under chronic itch conditions and in cultured keratinocyte HaCaT cells and mice skin keratinocytes. The ELISA test showed that the level of LCN2 increased significantly in plasma but not in DRG tissue, from both acetone-ether-water (AEW) induced dry skin and imiquimod (IMQ) induced psoriasis model mice. Current clamp recording demonstrated that LCN2 induced hyperexcitability in dorsal root ganglia neurons, which could be abolished by HS024, the inhibitor of melanocortin receptor 4 (MC4R). In addition, pharmacological inhibition of transient receptor potential vanilloid 1 (TRPV1) or TRPV1 knockout blocked LCN2-induced hyperexcitability in DRG neurons. In conclusion, this study demonstrated that keratinocyte ER stress is involved in chronic itch genesis by releasing LCN2, which sensitized primary sensory neurons via TRPV1. These findings suggested that inhibition of ER stress in keratinocytes could be a promising therapeutic strategy for treating chronic itch.

Keywords

Itch; Keratinocyte; Endoplasmic reticulum stress; LCN2; TRPV1

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