Acupuncture alleviates osteoarthritis pain by remodeling the DRG neuro-immune microenvironment via Piezo2-mediated macrophage polarization.

BACKGROUND: Osteoarthritis (OA) pain is predominantly characterized by mechanical allodynia, and dorsal root ganglion (DRG) neuro-immune crosstalk serves as a critical driver of peripheral sensitization. Acupuncture at ST36 produces robust analgesia, yet the mechanism by which peripheral mechanical stimulation translates into DRG immune regulation remains unclear. Here we investigated whether acupuncture alleviates OA pain by modulating Piezo2-dependent neuro-immune interactions. METHODS: Monosodium iodoacetate (MIA) was injected into the knee joint to establish OA in mice. Manual acupuncture at ST36 was performed for 7 consecutive days. Pain behaviors, knee histopathology, and DRG immune profiles were assessed by von Frey test, OARSI scoring, flow cytometry, immunofluorescence, Western blot, Luminex assay, and RNA sequencing. Pharmacological inhibition (GsMTx4), GM-CSF neutralization, macrophage depletion, and AAV9-mediated Piezo2 activation in DRG neurons were used to verify causality. RESULTS: Acupuncture significantly elevated mechanical paw withdrawal thresholds and attenuated cartilage destruction in OA mice. It did not alter systemic inflammatory cytokines but specifically normalized the DRG neuro-immune microenvironment: downregulating Piezo2 in knee-innervating DRG sensory neurons, reducing pro-inflammatory mediators including GM-CSF, and increasing the CD206-positive/M2-like macrophage phenotype. Inhibition of Piezo channels or neutralization of GM-CSF mimicked acupuncture analgesia, whereas DRG-specific Piezo2 activation recapitulated immune dysregulation and mechanical hypersensitivity. In vitro, conditioned medium from Piezo2-inhibited DRG neurons promoted a CD206-positive macrophage phenotype in bone marrow-derived macrophages. CONCLUSION: These findings reveal a novel neuro-immune mechanism underlying acupuncture analgesia. Acupuncture suppresses Piezo2 expression in DRG sensory neurons, reduces inflammatory mediators including GM-CSF, and reshapes the DRG immune microenvironment toward anti-inflammatory macrophage polarization. Our study identifies Piezo2 as a key mechanotransducer linking acupuncture to DRG neuro-immune modulation, providing a potential therapeutic target for OA pain.