VSIG4 Inhibits Microglia-Mediated Neuroinflammation and Neuronal Injury by Modulating the JAK2-STAT3/NF-κB Signaling Pathway in Parkinson's Disease.

V-set and immunoglobulin domain-containing 4 (VSIG4) was found to regulate microglial inflammation and oxidative stress in our previous study. This study aimed to further explore the effect and mechanism of VSIG4 on neuroinflammation and neuronal injury in Parkinson's disease (PD). Mouse microglia were infected with VSIG4-overexpressing adeno-associated virus (AAV) or shRNA AAV or VSIG4-overexpressing AAV with or without AZD1480 (a JAK inhibitor). Furthermore, a coculture system was established, where mouse dopamine neurons were cocultured with the infected microglia or their culture medium under the presence of α-synuclein. PD mice were treated with VSIG4-overexpressing AAV, with or without AZD1480. In microglia, VSIG4 overexpression inhibited the release of tumor necrosis factor-α, interleukin-6, and interleukin-1β and modulated the JAK2-STAT3/NF-κB pathway, but its knockdown had the opposite effect. In the coculture system, VSIG4-overexpressing microglia promoted dopamine neuron viability but suppressed p-α-synuclein and neuron apoptosis, whereas VSIG4-knockdown microglia presented the opposite effect. The culture medium of VSIG4-modified microglia had a similar effect on dopamine neuron functions to that of VSIG4-modified microglia. In PD mice, VSIG4 was insufficiently expressed in microglia, while VSIG4 overexpression improved the performances in open field and pole tests, promoted dopamine neuron viability and dopamine transport, and suppressed p-α-synuclein and neuroinflammation. Moreover, the addition of AZD1480 attenuated the effects of VSIG4 overexpression both in vitro and in vivo. VSIG4 ameliorates microglia-mediated neuroinflammation and neuronal injury via the JAK2-STAT3/NF-κB pathway in PD, shedding light on its supplementation as a potential treatment option for PD.