Arterial macrophage cholesterol accumulation and impaired cholesterol efflux lead to foam cell formation and the development of atherosclerosis. Modified lipoproteins interact with toll-like receptors (TLR), causing an increased inflammatory response and altered cholesterol homeostasis. We aimed to determine the effects of TLR antagonists on cholesterol efflux and foam cell formation in human macrophages. Stimulated monocytes were treated with TLR antagonists (MIP2), and the cholesterol efflux transporter expression and foam cell formation were analyzed. The administration of MIP2 attenuated the foam cell formation induced by lipopolysaccharides (LPS) and oxidized low-density lipoproteins (ox-LDL) in stimulated THP-1 cells (p < 0.001). The expression of ATP-binding cassette transporters A (ABCA)-1, ABCG-1, scavenger receptor (SR)-B1, liver X receptor (LXR)-α, and peroxisome proliferator-activated receptor (PPAR)-γ mRNA and proteins were increased (p < 0.001) following MIP2 administration. A concentration-dependent decrease in the phosphorylation of p65, p38, and JNK was also observed following MIP2 administration. Moreover, an inhibition of p65 phosphorylation enhanced the expression of ABCA1, ABCG1, SR-B1, and LXR-α. TLR inhibition promoted the cholesterol efflux pathway by increasing the expression of ABCA-1, ABCG-1, and SR-B1, thereby reducing foam cell formation. Our results suggest a potential role of the p65/NF-kB/LXR-α/ABCA1 axis in TLR-mediated cholesterol homeostasis.

Background: Cardiovascular disease (CVD) is a major complication of systemic lupus erythematosus (SLE). This study compared several CV risk scores in Korean female patients with SLE and searched for an association with subclinical atherosclerosis and lipid metabolism. Methods: Female SLE patients and healthy controls (HCs) underwent carotid ultrasonography and pulse wave velocity (PWV), and serum efflux cholesterol capacity was measured. The Framingham risk scores (FRSs), American College of Cardiology/American Heart Association (ACC/AHA) scores, and Korean Risk Prediction Model (KRPM) scores were calculated. Results: While carotid intima-media thickness (IMT) and the prevalence of carotid plaque did not differ between 67 SLE patients and 37 HCs, carotid plaque scores were higher in SLE patients compared with HCs. While the FRS and the ACC/AHA CV risk scores did not differ, the KRPM scores were higher in SLE patients. The carotid IMT, plaque score, and PWV were correlated with the FRS, ACC/AHA CV risk, and KRPM score in SLE patients. SLE patients with carotid plaque had higher FRS, ACC/AHA CV risk, and KRPM scores than those without carotid plaque. In addition, the serum cholesterol efflux capacity did not differ between SLE patients with and without carotid plaque but was correlated with carotid IMT. Conclusions: The scores obtained from the CV risk-prediction models were correlated with subclinical atherosclerosis in SLE. A cardiovascular risk assessment tool developed specifically for Koreans is suitable for evaluating the CV risk in Korean SLE patients.