The Key Role of NF-κB Signaling Pathway in Mediating Cholesterol Efflux and Pyroptosis in ox-LDL-induced Macrophages-derived Foam Cells

Abstract Objective NF-κB plays a well-known function in the regulation of immune responses and inflammation, but growing evidences support a major role in atherosclerosis. Currently, the regulatory mechanism of NF-κB pathway involved in atherosclerosis is not clear.Methods To investigate the role of ox-LDL in NF-κB regulation, the protein expression of phosphorylated NF-κB, a marker of NF-κB pathway activation was measured. The pyroptosis of macrophage was evaluated by western blot and fluorescence microscope. Cholesterol efflux capacity was determined by fluorescence assay and oil red O staining. The inhibitor of activation of NF-κB signal was used to assess the effect of NF-κB signal on macrophage pyroptosis as well as cholesterol efflux in macrophage. Small interfering RNA of ABCA1 was used to assess the effect of ABCA1 on macrophage pyroptosis.Results In this study, we reported THP-1 derived macrophage can be stimulated to increase pyroptosis by ox-LDL in a concentration-dependent. Macrophage pyroptosis was correlated with enhanced activation of NF-κB signal. We found that using inhibitor of NF-κB phosphorylation to attenuate activation of NF-κB signal could decrease macrophage pyroptosis and ox-LDL-induced cholesterol efflux disorder. Furthermore, we found that knocking out of ABCA1 led to increased cell inflammation death. But pyroptosis was blocked, may led to cholesterol efflux dysfunction. Conclusion This study demonstrates that the mechanism of NF-κB involved in the development of atherosclerosis is depending on mediating cell pyroptosis and cholesterol efflux for the first time and provides significant light on macrophage NF-κB signal in atherosclerosis. In addition, ABCA1 may be involved in the development of atherosclerosis as a bridge between cholesterol efflux and pyroptosis in macrophages.