Interferon Regulatory Factor 5 Regulates the Phagocytosis of Microglia and Alleviate Alzheimer’s Pathology

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.