A20, as a downstream factor of Nrf2, is involved in the anti-neuroinflammatory and antidepressant-like effects of luteolin

Abstract

• Luteolin exerted anti-neuroinflammatory and antidepressant-like effects. • Luteolin upregulated the expression of A20 and Nrf2. • Upregulation of A20 and Nrf2 was involved in the inhibitory effects of luteolin on neuroinflammation. • A20, as a downstream factor of Nrf2, was involved in the inhibitory effects of luteolin on activation of microglia. Microglia-mediated neuroinflammation is closely related to depression. Many studies have shown that the NF-κB pathway was involved in the anti-neuroinflammatory effects of luteolin. However, more detailed molecular mechanisms should be further studied. In this study, our data indicated that luteolin inhibited neuroinflammation and alleviated depression-like behavior in a lipopolysaccharide (LPS)-induced mouse model. Further investigation revealed that luteolin increased the expression of A20 and Nrf2 and decreased the expression of TRAF6 while removing K63-linked polyubiquitin chains from TRAF6. Knockdown treatment using siRNA-A20 or Nrf2 reversed the effects of luteolin on neuroinflammation. This study explored the novel mechanism by which luteolin exerted anti-neuroinflammatory and antidepressant-like effects in a lipopolysaccharide-induced mouse model, which might be related to the upregulation of A20 and Nrf2. Notably, A20 exerted its function as a downstream factor of Nrf2. This study provides evidence for the potential application of luteolin in the prevention and treatment of neuroinflammation and depression.