Microglial Macrophage-Derived Ds-HMGB1 in DRG Orchestrates Neuropathic Pain Through Immune-Neural Signaling

Neuroimmune crosstalk in the dorsal root ganglion (DRG) plays a pivotal role in neuropathic pain driven by chemotherapy-induced peripheral neuropathy (CIPN). This study shows 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-TRMPhi) 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 NF-KappaB-dependent upregulation of transient receptor potential vanilloid 1 (TRPV1) and amplifying mechanical allodynia. PDIA3, GSDMD, or ds-HMGB1 inhibition alleviates pain without compromising oxaliplatins antitumor efficacy. Serum ds-HMGB1 correlates with pain severity in oxaliplatin-treated patients. M-TRMPhi-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.