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Zinc Ameliorates LPS-Induced Depressive-Like Behaviors Via Modulating Microglial Polarization
ChenQi Li1,2, Gen Miao1, Wenjing Shi1
1Department of Nutrition and Food Hygiene, Naval Medical University, Shanghai, 200433, China.
Abstract:
The neuroinflammation plays a crucial role in the pathogenesis and progression of depression. Microglia serve as the principal source of neuroinflammatory factors and regulate neuroinflammation via M1 and M2 polarization phenotypes. Moreover, NOD like receptor protein 3 (NLRP3) inflammasome pathway is considered to be important in regulating pro-inflammatory cytokine release in the hippocampus. Zinc supplementation has been shown to effectively alleviate depressive symptoms in patients. In this study, we utilized a lipopolysaccharide (LPS)-induced mouse model of depression and LPS-activated BV-2 cells to examine the impact of zinc supplementation. The findings indicated that zinc supplementation could: (1) ameliorate the depressive-like behaviors of the mouse model with inhibition of inflammatory cytokines and zinc homeostasis recovery. (2) induce the polarization of microglia towards the M2 phenotype in vivo and in vitro. (3) suppress the activation of the NLRP3 inflammasome pathway by impeding the expression of P2X purinergic receptor 7 (P2 × 7) induced by LPS, thereby regulating microglial polarization. This may represent a crucial pathway via which zinc inhibits the M1 polarization of microglia, promotes polarization towards the M2 phenotype, thus improving neuroinflammation and exerting an antidepressant effect.
Insights
Zinc supplementation alleviates depression by reducing neuroinflammation. It shifts microglia to an anti-inflammatory M2 phenotype and suppresses the NLRP3 inflammasome pathway, offering a novel therapeutic approach.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Neuroinflammation, driven by microglia, is key in depression pathogenesis.
- The NLRP3 inflammasome pathway and microglial M1/M2 polarization are critical regulators of neuroinflammation.
- Zinc supplementation shows promise in alleviating depressive symptoms.
Purpose of the Study:
- To investigate the effects of zinc supplementation on a lipopolysaccharide (LPS)-induced mouse model of depression and BV-2 cells.
- To elucidate the mechanisms underlying zinc's antidepressant effects, focusing on neuroinflammation and microglial polarization.
Main Methods:
- Utilized an LPS-induced mouse model of depression and LPS-activated BV-2 microglial cells.
- Assessed depressive-like behaviors, inflammatory cytokine levels, zinc homeostasis, microglial polarization (M1/M2), and NLRP3 inflammasome activation.
- Examined the role of P2X7 receptor in LPS-induced NLRP3 inflammasome activation.
Main Results:
- Zinc supplementation ameliorated depressive-like behaviors, reduced inflammatory cytokines, and restored zinc homeostasis in the mouse model.
- Zinc induced microglial polarization towards the M2 phenotype both in vivo and in vitro.
- Zinc suppressed LPS-induced NLRP3 inflammasome activation by impeding P2X7 receptor expression, thereby regulating microglial polarization.
Conclusions:
- Zinc supplementation exerts antidepressant effects by mitigating neuroinflammation.
- Zinc promotes M2 microglial polarization and inhibits M1 polarization via suppression of the NLRP3 inflammasome pathway.
- Targeting zinc homeostasis and microglial polarization presents a potential therapeutic strategy for depression.
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