Nerve Modulation Therapy in Gouty Arthritis: Targeting Increased SFRP2 Expression in Dorsal Root Ganglion Regulates Macrophage Polarization and Alleviates Endothelial Damage

Gouty arthritis (GA) is a form of arthritis caused by uric acid deposition in the joints that result in intense inflammation and pain. Accumulating evidence showed the importance of the sensory neurons signal upon immune cells by releasing neuropeptides and chemokines to regulate associated immune-inflammatory response. In this study, we investigated the significance of sensory neuron neuropeptides and chemokine signals on inflammation-induced macrophages polarization during GA. : We screened the mRNA expression profile during GA in dorsal root ganglion (DRG) neurons to identify the most likely candidate that mediates the neuro-immune communication. Then, we silenced specific gene expression in the DRG by lentiviral vectors in the monosodium urate (MSU)-induced ankle GA mouse model and evaluated alterations in the inflammatory response. In vitro, primary macrophages were used to investigate the neural impact on M1/M2 subtype polarization, proinflammatory cytokine production and downstream endothelial damage. Mechanism by which macrophage inflammation is induced in the DRG was evaluated by Western blot, immunofluorescence, and immunoprecipitation. : We found that secreted frizzled-related protein 2 (sFRP2) was the most upregulated gene in dorsal root ganglion (DRG) neurons in response to monosodium urate (MSU) deposition. Injection of LV-sFRP2-shRNA into the L4 and L5 DRG significantly suppressed inflammatory cell infiltration and M1 polarization in the synovial membrane, attenuating hyperalgesia and ankle swelling in the GA mouse model. In vitro, DRG neurons-derived sFRP2 promoted M1 polarization and macrophage migration, thereby upregulating the production of proinflammatory cytokines and preventing endothelial apoptosis. Furthermore, DRG-derived sFRP2 activated the nuclear factor (NF)-κB pathway by destabilizing the β-catenin and p65 complex. : We demonstrated the involvement of a sensory neuron-macrophage axis in GA pathology that was regulated by sFRP2 expression in a paracrine manner. Targeting increased sFRP2 expressions in DRG provide novel insights for future GA research in both pain alleviation and treatment of gout inflammation.