Regulation of Atherosclerosis by Toll-Like Receptor 4 Induced by Serum Amyloid 1: A Systematic In Vitro Study.

The objective of this study was to investigate the effects of serum amyloid 1 (SAA1) on activation of endothelial cells, formation of foam cells, platelet aggregation, and monocyte/platelet adhesion to endothelial cells. The effect of SAA1 on the inflammatory activation of endothelial cells was investigated by detecting the expression of inflammatory factors and adhesion molecules. The role of SAA1 in formation of foam cells was verified by detecting lipid deposition and expression of molecules related to the formation of foam cells. After platelets were stimulated by SAA1, the aggregation rate was evaluated to determine the effect of SAA1 on platelet aggregation. Monocytes/platelets were cocultured with human umbilical vein endothelial cells (HUVECs) pretreated with or without SAA1 to determine whether SAA1 affected monocyte/platelet adhesion to endothelial cells. By inhibiting toll-like receptor 4 (TLR4) function, we further identified the role of TLR4 signaling in SAA1-mediated endothelial inflammatory activation, foam-cell formation, and monocyte/platelet adhesion to HUVECs. SAA1 significantly increased the expression of adhesion molecules and inflammatory factors in HUVECs. Moreover, SAA1 also promoted lipid deposition and the expression of inflammatory factors and low-density lipoprotein receptor-1 (LOX-1) in THP-1-derived macrophages. In addition, SAA1 induced platelet aggregation and enhanced monocyte/platelet adhesion to HUVECs. However, the TLR4 antagonist significantly inhibited SAA1-induced endothelial cell activation, foam-cell formation, and monocyte/platelet adhesion to HUVECs and downregulated the expression of myeloid differentiation factor 88 (MyD88), phosphor-inhibitor of nuclear factor κB kinase subunit α/ß (P-IKKα/ß), phospho-inhibitor of nuclear factor κB subunit α (P-IKBα), and phosphorylation of nuclear transcription factor-κB p65 (P-p65) in SAA1-induced HUVECs and THP-1 cells. Conclusively, it is speculated that SAA1 promotes atherosclerosis through enhancing endothelial cell activation, platelet aggregation, foam-cell formation, and monocyte/platelet adhesion to endothelial cells. These biological functions of SAA1 may depend on the activation of TLR4-related nuclear factor-kappa B (NF-κB) signaling pathway.

[Pexidartinib inhibits the aggregation of monocytes into tumor microenvironment and reduces the number of M2 tumor-associated macrophages].

Objective To explore the effect of pexidartinib on the recruitment of monocytes into the tumor microenvironment and the polarization of M2 macrophages. Methods The colon cancer mouse model was established with the subcutaneous rejection of MC38 cells. After the tumor-bearing mice were treated with pexidartinib, we observed the effects of pexidartinib on the tumor growth, the survival of tumor-bearing mouse and the number of intratumoral tumor-associated macrophages (TAMs). Peripheral blood mononuclear cells were isolated from the enhanced green fluorescent protein (EGFPTg/+) transgenic mice and then transferred into the tumor-bearing mice via tail vein. After the tumor-bearing mice were treated with pexidartinib, the monocyte recruitment and the proportions of F4/80 and CD206-positive cells were detected by the immunofluorescence and flow cytometry. Results Pexidartinib alleviated the growth of MC38 cells in vivo and improved the survival rate in tumor-bearing mice. Pexidartinib reduced the number of TAMs and the formation of M2 TAMs in the tumor microenvironment, and inhibited the recruitment of monocytes from peripheral blood to the tumor microenvironment. Conclusion Pexidartinib can inhibit the tumor growth by suppressing the aggregation of macrophages and the number of M2 TAMs in the tumor microenvironment.