Paeonol enhances macrophage phagocytic function by modulating lipid metabolism through the P53-TREM2 axis
Introduction: The emerging concept of immunometabolism highlights the interplay between lipid metabolism and phagocytosis in macrophages. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) has been identified as an essential modulator of both lipid metabolism and phagocytic function in macrophages. This study aims to investigate the roles of P53 and TREM2 in regulating macrophage lipid metabolism and phagocytosis and to evaluate the potential therapeutic effects of paeonol on these processes. Methods: CRISPR-Cas9 was utilized to generate P53 and TREM2 knockout RAW264.7 cell lines. The dual-luciferase reporter gene assay was performed to assess the interaction between P53 and the TREM2 promoter. A series of functional assays were conducted to evaluate the impact of P53 and TREM2 on macrophage lipid metabolism and phagocytic function. The effects of Paeonol on these processes were also examined. Results: Our findings revealed that paeonol induces the accumulation of P53 in the nucleus. P53 acts as a transcription factor that upregulates the expression of TREM2, promoting macrophage lipid metabolism, metabolic activity, and phagocytic capacity. Additionally, dual-luciferase reporter gene assays confirmed the interaction between P53 and the TREM2 promoter. Discussion: This study provides novel insights into the roles of P53 and TREM2 in regulating macrophage lipid metabolism and phagocytic function. Further research is warranted to explore the potential applications of Paeonol and to elucidate the molecular mechanisms underlying the observed effects.
GRAPHICAL ABSTRACT In this illustration, we depict a three-step process involving the roles of paeonol, TREM2, and ATP in macrophage function. Firstly, paeonol inhibits the export of P53 from the cell nucleus, leading to its accumulation within the nucleus. This, in turn, increases the likelihood of P53 binding to the TREM2 promoter, subsequently enhancing the expression of TREM2. Secondly, as TREM2 expression increases, it promotes lipid metabolism in macrophages. This enhancement of lipid metabolism subsequently leads to elevated levels of ATP. Lastly, with the increase in ATP levels, the phagocytic function of macrophages is enhanced, contributing to a more efficient immune response.