Oxidative Stress and Neuroinflammation Potentiate Each Other to Promote Progression of Dopamine Neurodegeneration

Figure 1

Crosstalk between oxidative stress and neuroinflammation in the progression of PD. Oxidative stress and neuroinflammation played synergistic roles in the development of PD. First, ROS increased during oxidative stress. Continuous exposure to ROS led to mtDNA mutation, and mtDNA mutation accumulation enhanced ROS production, forming a positive feedback loop. On the one hand, defective mitochondria released their contents to trigger an innate immune response. Next, oxidative mtDNA mediated the activation of NLRP3 inflammasome to generate cytokines to induce neuroinflammation. Moreover, there were three signaling pathways that played key roles in the PD process: NF-κB, Nrf2, and STAT3. After the inhibitory protein IκB that bound to NF-κB was degraded by ROS, NF-κB entered the nucleus and mediated inflammation. Nrf2 was also activated and entered the nucleus, which simultaneously generated anti-inflammatory and antioxidant properties. Activated STAT3 mediated the proinflammatory response of microglia to CNS injury, including promoting the secretion of inflammatory factors. Finally, there were resident glial cells in the brain: microglia and astrocytes. The former, as a marker of neuroinflammation, could be polarized to the M1/M2 phenotype with proinflammatory and anti-inflammatory effects. Moreover, microglia not only induced oxidative stress through NADPH oxidase- (NOX-) generated ROS but also prevented oxidative damage through high concentrations of GSH and Cu/ZnSOD. In addition, astrocyte-overexpressed DJ-1 exerted antioxidative stress and induced A1 astrocytes to polarize to A2 phenotype in hypoxic state to further produce GDNF to support neuron growth. Moreover, astrocytes were activated by microglia M1 phenotype to become astrocyte A1 phenotype, thus losing their protective functions. (The signals coming from microglia are contained in the light blue ellipse, while signals in the green ellipse are produced by astrocytes.)