Association of Electronegative LDL with Macrophage Foam Cell Formation and CD11c Expression in Rheumatoid Arthritis Patients

Abstract

L5, the most negatively charged subfraction of low-density lipoprotein (LDL), is implicated in atherogenesis, but the pathogenic association is relatively unexplored in patients with rheumatoid arthritis (RA). We examined the role of L5 LDL in macrophage foam cell formation and the association of L5 with CD11c expression in THP-1 cells and RA patients. Using quantitative real-time PCR, we determined mRNA expression levels of ITGAX, the gene for CD11c, a marker associated with vascular plaque formation and M1 macrophages in atherogenesis, in 93 RA patients. We also examined CD11c expression on THP-1 cells treated with L5 by flow cytometry analysis and the plasma levels of inflammatory mediators using a magnetic bead array. We found a dose-dependent upregulation of foam cell formation of macrophages after L5 treatment (mean ± SEM, 12.05 ± 2.35% in L5 (10 µg/mL); 50.13 ± 3.9% in L5 (25 µg/mL); 90.69 ± 1.82% in L5 (50 µg/mL), p < 0.01). Significantly higher levels of CD11c expression were observed in 30 patients with a high percentage of L5 in LDL (L5%) (0.0752 ± 0.0139-fold) compared to 63 patients with normal L5% (0.0446 ± 0.0054-fold, p < 0.05). CD11c expression levels were increased in the L5-treated group (30.00 ± 3.13% in L5 (10 µg/mL); 41.46 ± 2.77% in L5 (50 µg/mL), p < 0.05) and were positively correlated with plasma levels of interleukin (IL)-6 and IL-8. L5 augmented the expression of IL-6, IL-8, and tumor necrosis factor-α (TNF-α) on monocytes and macrophages. Our findings suggest that L5 may promote atherogenesis by augmenting macrophage foam cell formation, upregulating CD11c expression, and enhancing the expression levels of atherosclerosis-related mediators.

Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies

“…In three comprehensive studies, researchers have recently shown that circulating L5 levels are significantly increased in patients with RA or SLE whose plasma LDL-C levels are equal to or lower than those of healthy control individuals [ 56 , 57 , 86 ]. In a cohort of patients with RA, the plasma L5% and L5 concentration were significantly higher in those with subclinical atherosclerosis than in those without it, despite similar LDL-C levels among all the study participants [ 56 ].…”

“…The plasma L5% and L5 concentration were also positively correlated with the extent of carotid artery atherosclerosis reflected by the intima–media thickness (IMT), disease activity score, and 10-year ASCVD risk score [ 56 ]. Further investigation revealed that L5 contributes to atherogenesis by augmenting macrophage foam cell formation, upregulating integrin CD11c expression, and enhancing inflammatory mediators including IL-6, IL-8, and tumor necrosis factor (TNF)-α [ 86 ]. These findings provide a mechanistic link between L5 and ASCVD development and clinical manifestations [ 56 , 57 , 79 , 86 ].…”

“…Further investigation revealed that L5 contributes to atherogenesis by augmenting macrophage foam cell formation, upregulating integrin CD11c expression, and enhancing inflammatory mediators including IL-6, IL-8, and tumor necrosis factor (TNF)-α [ 86 ]. These findings provide a mechanistic link between L5 and ASCVD development and clinical manifestations [ 56 , 57 , 79 , 86 ]. Most importantly, both L5% and L5 concentration declined significantly after six months of DMARD therapy in RA patients [ 56 ], suggesting the dynamic and reversible nature of L5 formation.…”

“…Given a bidirectional link between LOX-1 and PCSK9, especially in an inflammatory status [ 129 ], a PCSK9 inhibitor could reduce LOX-1 expression. L5 is a promising marker for predicting ASCVD [ 56 , 57 , 86 ]. The therapeutic goal of controlling L5 should be to lower its plasma concentration below 1.7 mg/dL.…”

Research of Pathogenesis and Novel Therapeutics in Arthritis 2.0

“…The study researchers discuss the significance of the immune system reaction to a foreign antigen and the impact on inflammatory cells in OA [12]. Chang and colleagues describe findings suggesting that electronegative low-density lipoprotein (LDL) may promote atherogenesis by augmenting macrophage foam cell formation, upregulating CD11c expression, and enhancing the expression levels of atherosclerosis-related mediators in RA [13]. In another study, Hähnlein and colleagues discuss evidence suggesting that human lymph node stromal cells (LNSCs) from RA patients regulate peripheral tolerance, making these cells a novel target to exploit in tolerance maintenance and induction [14].…”