Dorsal Root Ganglion Neuron-Derived sFRP2 Promotes Macrophage Polarization to Regulate Gouty Arthritis

Abstract

Background: Gouty arthritis (GA) is a form of arthritis caused by uric acid deposition in the joints that results in intense inflammation and pain. We investigated the significance of sensory neuron neuropeptide and chemokine signals on inflammation-induced macrophages during GA. Methods: First, 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. Findings: Secreted frizzled-related protein 2 (sFRP2) was the most upregulated gene in DRG neurons in GA mice. Interestingly, injection of LV-sFRP2-shRNA into the L5 and S1 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, conditioned medium from sFRP2 knockdown DRG neurons inhibited M1 polarization and macrophage migration, thereby downregulating 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. Interpretation: We demonstrated the involvement of a sensory neuron-macrophage axis in GA pathology that is regulated by sFRP2 expression in a paracrine manner. Funding Statement: Funding: This work was supported by the National Natural Science Foundation of China (81672205), National Key R&D Programme (2016YFC1102100) and the Shanghai Science and Technology Development Fund (18DZ2291200, 18441902700). Declaration of Interests: No competing interests declared. Ethics Approval Statement: The Institution of Animal Care and Use Committee (IACUC) of Shanghai Ninth Hospital reviewed and approved all the animal care protocols and experimental procedures. All mice in the study were allowed ad libitum access to food and water prior to and throughout the experimental protocol.