Notch/NICD/RBP-J signaling axis regulates M1 polarization of macrophages mediated by advanced glycation end products

AbstractAdvanced glycation end products (AGEs) aggregation and macrophages polarization are identified as the main factors contributing to bone diseases caused by aging or diabetes, such as senile or diabetic osteoporosis. Here, we aimed to elucidate the involvement and potential mechanism of AGEs in macrophages polarization and osteoclastogenesis. Firstly, AGEs-treated RAW264.7 macrophages were observed to up-regulate the release of nitric oxide (NO), the expression of M1-associated genes and the surface antigen marker CD86. The detection of osteoclast-related markers and TRAP staining revealed that the osteoclastogenic ability of M1 macrophages was markedly enhanced by AGEs. Further, AGEs were found to effectively activate the transduction of Notch signaling pathway and promote the nuclear translocation of NICD1. In addition, with the signals transduction of Notch pathway blocked by γ-secretase inhibitor DAPT and siRNA targeting silencing RBP-J, AGEs-induced M1 polarization was significantly mitigated. Collectively, we defined a critical role for AGEs in inducing M1 polarization and osteoclastogenesis of macrophages, and further identified Notch/NICD/RBP-J signaling axis as an essential mechanism regulating AGEs-mediated M1 polarization.
Source: Glycoconjugate Journal - Category: Biochemistry Source Type: research