Nie Huimin, Liu Boyu, Yin Chengyu, Dong Zishan, Pan Yushuang, Li Peiyi, Hu Qimiao, Wang Jie, Tai Yan, Shao Xiaomei, Tian Guihua, Wang Chuan, Fang Jianqiao, Liu Boyi
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.
Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Sci Adv. 2025 Aug;11(31):eadu4270. doi: 10.1126/sciadv.adu4270. Epub 2025 Aug 1.
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.
Ⅰ型复杂性区域疼痛综合征（CRPS-Ⅰ）在初次受伤后发病。它会导致长时间的疼痛，这种疼痛在组织愈合的正常预期时间之后仍会持续。CRPS-Ⅰ疼痛慢性化的潜在机制尚不清楚。在此，我们发现在CRPS-Ⅰ大鼠模型的局部背根神经节（DRG）中存在巨噬细胞的长期浸润。我们证明，再生胰岛衍生蛋白3β（Reg3β）在模型建立后由DRG神经元特异性产生，并作为一种重要的信号分子驱动促炎性巨噬细胞浸润到局部DRG中。浸润的巨噬细胞产生肿瘤坏死因子-α（TNF-α），这会导致伤害性DRG神经元的兴奋性过高，进而促进Reg3β从DRG神经元中的过表达和分泌，以募集更多的巨噬细胞。我们的研究揭示了一种由神经元Reg3β/巨噬细胞TNF-α传递的正反馈信号，该信号导致DRG中的神经炎症，从而在CRPS-Ⅰ大鼠模型中产生持续性疼痛。这一发现为局部DRG中导致CRPS-Ⅰ疼痛慢性化的神经免疫相互作用提供了见解。
