Microglial macrophage-derived ds-HMGB1 in DRG orchestrates neuropathic pain through immune-neural signaling

  • Cell Rep. 2025 Dec 23;44(12):116671. doi: 10.1016/j.celrep.2025.116671.
Yang Yang  1 ,  Bing Zhao  2 ,  Jiege Huo  3 ,  Guoli Wei  3 ,  Xinyu Liu  2 ,  Hongli Lan  2 ,  Yuanzhe Wang  2 ,  Yue Hu  2 ,  Peng Cao  4
Affiliations
  • 1. State Key Laboratory of Technologies of Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: [email protected].
  • 2. State Key Laboratory of Technologies of Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
  • 3. Department of Oncology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
  • 4. State Key Laboratory of Technologies of Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China; Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: [email protected].
PMID: 41385369 DOI: 10.1016/j.celrep.2025.116671
Abstract

Neuroimmune crosstalk in the dorsal root ganglion (DRG) plays a pivotal role in neuropathic pain driven by chemotherapy-induced peripheral neuropathy (CIPN). Here, we report that the pro-inflammatory disulfide isoform of high-mobility group box 1 (ds-HMGB1) is a key mediator of oxaliplatin-induced neuropathic pain, with DRG microglia-like tissue-resident macrophages (M-TRMφs) as its primary reservoir. Mechanistically, protein disulfide isomerase A3 (PDIA3) catalyzes HMGB1 oxidation to ds-HMGB1 via Cys23-Cys45 bond formation, while gasdermin D (GSDMD)-mediated Pyroptosis drives its release. Released ds-HMGB1 engages Toll-like Receptor 4 (TLR4) on C2-subtype sensory neurons, triggering nuclear factor κB (NF-κB)-dependent upregulation of transient receptor potential vanilloid 1 (TRPV1) and amplifying mechanical allodynia. PDIA3, GSDMD, or ds-HMGB1 inhibition alleviates pain without compromising oxaliplatin's anti-tumor efficacy. Serum ds-HMGB1 correlates with pain severity in oxaliplatin-treated patients. M-TRMφ-derived ds-HMGB1 orchestrates neuropathic pain through pyroptotic release and TLR4/TRPV1 signaling in a redox-regulated macrophage-neuron axis in the DRG. ds-HMGB1 emerges as a potential biomarker and therapeutic target in CIPN.

Keywords
CIPN; CP: immunology; CP: neuroscience; GSDMD; M-TRMφ; ds-HMGB1; immune-neural signaling; neuropathic pain.
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