2. Academic Validation
  3. Neuronal Reg3β/macrophage TNF-α-mediated positive feedback signaling contributes to pain chronicity in a rat model of CRPS-I

Neuronal Reg3β/macrophage TNF-α-mediated positive feedback signaling contributes to pain chronicity in a rat model of CRPS-I

  • Sci Adv. 2025 Aug;11(31):eadu4270. doi: 10.1126/sciadv.adu4270.
Huimin Nie 1,  Boyu Liu 1,  Chengyu Yin 1 2,  Zishan Dong 3,  Yushuang Pan 1,  Peiyi Li 1,  Qimiao Hu 1,  Jie Wang 4,  Yan Tai 5,  Xiaomei Shao 1,  Guihua Tian 6,  Chuan Wang 7 8,  Jianqiao Fang 1,  Boyi Liu 1
Affiliations

Affiliations

  • 1 Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Zhejiang Chinese Medical University, Hangzhou, China.
  • 2 Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Pathophysiology, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Hebei Medical University, Shijiazhuang, China.
  • 4 Department of Rehabilitation in Traditional Chinese Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, China.
  • 6 Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 7 Department of Pharmacology, Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, China.
  • 8 College of Pharmaceutical Sciences, Hebei University, Baoding, China.
PMID: 40749060 DOI: 10.1126/sciadv.adu4270
Abstract

Complex regional pain syndrome type I (CRPS-I) develops after an initial injury. It causes prolonged pain that persists beyond the usual expected time for tissue healing. Mechanisms underlying pain chronicity of CRPS-I remain unknown. Here, we identified the presence of long-lasting infiltration of macrophages in local dorsal root ganglia (DRG) of a rat model of CRPS-I. We demonstrate that regenerating islet-derived 3β (Reg3β) is specifically produced by DRG neurons upon model establishment and functions as an important signaling molecule to drive proinflammatory macrophage infiltration in local DRG. Infiltrated macrophages produce TNF-α, which causes hyperexcitability of nociceptive DRG neurons and reciprocally promotes Reg3β overexpression and secretion from DRG neurons to recruit more macrophages. Our work reveals a positive feedback signaling conveyed by neuronal Reg3β/macrophage TNF-α that contributes to neuroinflammation in DRG, resulting in persistent pain in a rat model of CRPS-I. This finding provides insights into the neuroimmune interaction in local DRG that contributes to pain chronicity of CRPS-I.

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