Abstract
Fluoxetine is a classic antidepressant drug, and its immunomodulatory effects have recently been reported in many disease models. In addition, it has strong antineuroinflammatory effects in stroke and neurodegenerative animal models. However, the effect of fluoxetine on microglia phagocytosis and its molecular mechanisms have not yet been studied. In this study, we investigated whether fluoxetine has a regulatory effect on microglial function. Microglia cell lines and primary mouse microglia were treated with fluoxetine, and the production of inflammatory cytokines and neurotrophic factors and the phagocytosis of amyloid β were measured. Fluoxetine significantly attenuated the production of lipopolysaccharide-induced proinflammatory cytokines and oxidative stress in microglia. Fluoxetine also significantly potentiated microglia phagocytosis and autophagy. In addition, autophagy flux inhibitors attenuated fluoxetine-induced phagocytosis. In conclusion, fluoxetine induces autophagy and potentiates phagocytosis in microglia, which can be a novel molecular mechanism of the neuroinflammatory and neuroprotective effects of fluoxetine.
Highlights
Microglia are innate immune cells of the central nervous system (CNS), and resting microglia in the mature brain are known to play a role in brain homeostasis (Lenz and Nelson, 2018)
When BV-2 cells were treated with LPS, nitric oxide (NO) increased, and when fluoxetine was treated with LPS, NO production was significantly inhibited in a concentrationdependent manner
Fluoxetine treatment significantly reduced TNF-α mRNA production, an inflammatory cytokine in BV-2 (Figures 1C, D), but no significant differences in the expression of Arg1, an M2 microglia marker, and brain-derived neurotrophic factor (BDNF), a neurotrophic factor, were observed
Summary
Microglia are innate immune cells of the central nervous system (CNS), and resting microglia in the mature brain are known to play a role in brain homeostasis (Lenz and Nelson, 2018). Activated microglia produce many proinflammatory and neurotoxic factors (Jha et al, 2018; Song et al, 2019; Gupta et al, 2020). These proinflammatory cytokines and molecules produced by these inflammatory activated microglia cause neuroinflammation, which can lead to neurodegenerative diseases (Ramirez et al, 2017; Hansen et al, 2018). Often known as M2 microglia, these cells can relieve inflammation through the secretion of anti-inflammatory molecules, mainly inhibit the production of proinflammatory cytokines, and release neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (Chen and Trapp, 2016). M2 microglia have been reported to clear tissue debris and misfolded proteins to maintain CNS homeostasis as CNS phagocytes
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