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Interferon Regulatory Factor 5 Regulates the Phagocytosis of Microglia and Alleviate Alzheimer's Pathology
Ziqi Fan1,2, Xinyi Zhang2, Shuai Zhao2
1Department of Neurology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Abstract:
Microglia play a critical role in the pathophysiology of Alzheimer's disease. They are involved in Aβ-induced neuroinflammatory responses, regulating the production of inflammatory mediators. Interferon regulatory factor 5 (IRF5) plays a central role in inflammatory diseases in the periphery, the role of which in central nervous system remains elusive. This study aimed to investigate the role of IRF5 in Aβ-induced neuroinflammation and the progression of Aβ pathology. We found that Aβ1-42 oligomers significantly increased the level of IRF5 in BV2 microglia. The levels of proinflammatory cytokines TNF-α, IL-1β, and IL-6 were significantly upregulated with Aβ treatment. IRF5 knockdown with siRNA in microglia significantly reduced the expression of these proinflammatory factors induced by Aβ and promoted Aβ phagocytosis. Besides, LC3 upregulation and p62 downregulation were observed in IRF5 knockdown microglia. This was also validated in APP/PS1 mice with IRF5 knockdown, leading to reduced Aβ levels in the brain. We conclude that IRF5 mediates Aβ-induced microglial inflammatory responses. IRF5 knockdown attenuated Aβ-induced inflammatory responses and promoted the phagocytosis and autophagy of Aβ by microglia.
Insights
Interferon regulatory factor 5 (IRF5) drives Alzheimer's disease inflammation in microglia. Reducing IRF5 lessens neuroinflammation and amyloid plaque buildup, offering a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglia are key players in Alzheimer's disease (AD) pathophysiology, mediating neuroinflammation.
- The role of Interferon regulatory factor 5 (IRF5) in central nervous system inflammation is not well understood.
- Amyloid-beta (Aβ) oligomers trigger inflammatory responses in microglia.
Purpose of the Study:
- To investigate the role of IRF5 in Aβ-induced neuroinflammation.
- To determine IRF5's impact on the progression of Aβ pathology in Alzheimer's disease.
Main Methods:
- Utilized BV2 microglia cell line and APP/PS1 transgenic mouse model.
- Administered Aβ1-42 oligomers to induce inflammatory responses.
- Employed small interfering RNA (siRNA) for IRF5 knockdown.
- Measured levels of IRF5, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), and Aβ.
- Assessed microglial phagocytosis and autophagy markers (LC3, p62).
Main Results:
- Aβ1-42 oligomers increased IRF5 levels and pro-inflammatory cytokine expression in microglia.
- IRF5 knockdown significantly reduced Aβ-induced inflammation and enhanced Aβ phagocytosis.
- IRF5 knockdown in microglia led to LC3 upregulation and p62 downregulation, indicating enhanced autophagy.
- IRF5 knockdown in APP/PS1 mice resulted in reduced brain Aβ levels.
Conclusions:
- IRF5 mediates Aβ-induced microglial inflammatory responses in Alzheimer's disease.
- Targeting IRF5 can attenuate neuroinflammation and promote Aβ clearance via phagocytosis and autophagy.
- IRF5 represents a potential therapeutic target for Alzheimer's disease treatment.
