Effect of Estrogen on Sirt1 Signaling in Human Macrophages

Cardiovascular diseases are the leading cause of human death worldwide. The role of the female hormone estrogen (E2) in this context is subject of debate. E2 might counteract inflammation by acting on macrophages; however, the underlying cellular mechanisms remain poorly understood. In the current study, we used primary human macrophages to investigate the effects of E2 on the NAD⁺-dependent deacetylase Sirt1, protein acetylation, and pro-inflammatory phenotype. Male and female primary monocytes from healthy adult individuals were polarized into pro-inflammatory M1 macrophages via treatment with LPS and IFN-γ followed by treatment with E2 for 24 h. While E2 treatment had no effect on the Sirt1 protein expression, it significantly increased the acetylation state of nuclear proteins p53 and Ku70. In addition, E2 increased NFκB-p65 expression exclusively in male M1 macrophages, while TNF-α was reduced in female M1 macrophages following E2 treatment. In male monocyte-like cells, E2 significantly reduced nuclear Sirt1 expression and increased Ku70 acetylation. The current study demonstrated that E2 treatment of human M1 macrophages leads to downregulation of nuclear Sirt1 and hyperacetylation of corresponding nuclear proteins. These molecular changes are associated with an enhancement of the pro-inflammatory phenotype in male primary macrophages, while an attenuation of inflammation was observed in female cells.