Fluoxetine Potentiates Phagocytosis and Autophagy in Microglia

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.

Schisandra chinensis (Turcz.) Baill. essential oil exhibits antidepressant-like effects and against brain oxidative stress through Nrf2/HO-1 pathway activation

“…SEO and H 2 O 2 were dissolved in DMSO to certain concentrations, and the concentrations were selected by our preliminary experiments, and data was not shown. Fluoxetine (15 μmol/L) served as positive control drug as previously reported (Han and Lee 2009 ; Park et al 2021 ).…”

Autophagy in the retinal neurovascular unit: New perspectives into diabetic retinopathy

“… 91 Similarly, autophagic flux and Atg gene expression in microglia were significantly inhibited by TLR4 activation by LPS in the study by Lee et al 92 Based on these findings, the antidepressant fluoxetine significantly decreased LPS‐induced inflammatory cytokine and oxidative stress production in microglia while increasing phagocytosis and autophagy. 93 In addition, diabetes‐induced neuroinflammation and microglial apoptosis can be prevented by administering melatonin, which activates autophagy in diabetic rats through the TLR4‐Akt–mTOR pathway. 94 Despite increased expression of Tnfa and Il1β, Igf1 deficiency‐induced autophagy protected structure and function of the retina in 6‐month‐old mice due to reduced inflammatory vesicle activation in the retina.…”

Microglia-mediated neuroinflammation and neuroplasticity after stroke

“…According to “eat me” or “don’t eat me” signals on the cellular surface, microglia start or cease the process of phagocytic clearance, which is critical for neuroinflammation resolution and neuro-reorganization (Chen et al, 2022 ). Song et al found that fluoxetine induces autophagy and potentiates phagocytosis in microglia, thereby exerting neuroprotection against LPS induced inflammation (Park et al, 2021 ). Microglia remove dead neurons and neuronal debris, which can serve as pro-inflammatory signals and disrupt CNS homeostasis (Brown, 2021 ).…”