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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
FPR2 deficiency alleviates LPS-induced depressive-like behaviors in mice by suppressing the microglial CSF1/NLRP3
Hanqi Wang1, Yijun Chen1, Junna Chang1
1Shanghai Frontiers Science Center of Drug Target Identification and Delivery, Engineering Research Center of Cell and Therapeutic Antibody, Ministry of Education, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, 200240, China.
Abstract:
Depression is one of the most prevalent psychiatric disorders worldwide, yet its pathogenesis remains unclear. Here, we aimed to investigate the effects of formyl peptide receptor 2 (FPR2), a key regulator of innate immunity and inflammation, on lipopolysaccharide (LPS)-induced depression-related behaviors in mice after intraperitoneal administration, and to elucidate its regulatory mechanisms in microglia. FPR2 knockout (Fpr2-/-) significantly attenuated LPS-induced depressive and anxiety-like behaviors in mice. LPS markedly increased FPR2 expression in microglia of the prefrontal cortex (PFC) and hippocampus, while only a minimal increase was observed in neurons. FPR2 deficiency alleviated LPS-induced microglial activation and reduced neuronal synaptic alterations. RNA sequencing and validation experiments confirmed that FPR2 deletion substantially decreased LPS-induced microglial NLRP3 inflammasome activation and IL-1β levels in the brain. Mechanistically, FPR2 regulated downstream NLRP3 activation by modulating CSF1, and FPR2/CSF1 activation was governed by its upstream ligand, serum amyloid A (SAA). Analysis of public clinical datasets revealed that SAA1 levels were significantly upregulated in the orbital ventral PFC of patients with major depressive disorder (MDD) and in the plasma of patients with late-life depression. These findings demonstrate that the SAA/FPR2/CSF1/NLRP3 pathway mediates LPS-induced depressive-like behaviors by regulating microglial activation and neuroinflammation.
Insights
Formyl peptide receptor 2 (FPR2) plays a key role in depression. Blocking FPR2 in mice reduced depression-like behaviors by decreasing neuroinflammation and microglial activation, suggesting a new therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Psychiatry
Background:
- Depression is a widespread psychiatric disorder with unclear causes.
- Formyl peptide receptor 2 (FPR2) is involved in innate immunity and inflammation.
- Microglia play a crucial role in neuroinflammation and brain disorders.
Purpose of the Study:
- To investigate the role of FPR2 in lipopolysaccharide (LPS)-induced depression-related behaviors in mice.
- To elucidate the regulatory mechanisms of FPR2 in microglia during LPS exposure.
- To explore the potential of targeting the FPR2 pathway for depression treatment.
Main Methods:
- Utilized a mouse model with FPR2 knockout (Fpr2-/-).
- Administered LPS intraperitoneally to induce depression-related behaviors.
- Analyzed microglial activation, neuronal synaptic alterations, and gene expression (RNA sequencing) in the prefrontal cortex and hippocampus.
- Measured NLRP3 inflammasome activation and IL-1β levels.
- Examined the role of CSF1 and serum amyloid A (SAA) in the pathway.
- Analyzed clinical datasets of patients with major depressive disorder (MDD).
Main Results:
- FPR2 knockout significantly reduced LPS-induced depressive and anxiety-like behaviors.
- LPS increased FPR2 expression in microglia, leading to activation and synaptic alterations.
- FPR2 deletion decreased microglial NLRP3 inflammasome activation and IL-1β levels.
- The SAA/FPR2/CSF1/NLRP3 pathway was identified as a key mediator.
- SAA1 levels were elevated in patients with MDD and late-life depression.
Conclusions:
- The SAA/FPR2/CSF1/NLRP3 pathway is crucial in mediating LPS-induced depressive-like behaviors.
- Targeting FPR2 in microglia can alleviate neuroinflammation and depressive symptoms.
- This pathway represents a potential therapeutic target for major depressive disorder.