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. 2020 Aug 16;21(16):5883.
doi: 10.3390/ijms21165883.

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

Ching-Kun Chang  1   2 , Po-Ku Chen  1   2   3 , Joung-Liang Lan  2   3   4 , Shih-Hsin Chang  2   3   5 , Tsu-Yi Hsieh  6 , Pei-Jyuan Liao  1   2 , Chu-Huang Chen  7   8 , Der-Yuan Chen  1   2   3   5
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Association of Electronegative LDL with Macrophage Foam Cell Formation and CD11c Expression in Rheumatoid Arthritis Patients

Ching-Kun Chang et al. Int J Mol Sci. .

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.

Keywords: CD11c expression; L5; atherosclerosis; macrophage foam cell; rheumatoid arthritis (RA).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effects of L5 on macrophage foam cell formation. THP-1 cells were incubated with (A) high-dose L5 (50 μg/mL), (B) midden-dose L5 (25 μg/mL), (C) low-dose L5 (10 μg/mL), (D) control (phosphate buffered saline, (E) high-dose L1 (50 μg/mL), (F) midden-dose L1 (25 μg/mL), and (G) low-dose L1 (10 μg/mL) for 48 h. (H) Difference in the proportion of macrophage foam cell formation among the different groups. Data are presented as the mean ± SEM for three independent experiments. * p < 0.05, determined by one-way ANOVA.
Figure 2
Figure 2
Comparison of CD11c (ITGAX) mRNA expression (A) between rheumatoid arthritis (RA) patients and healthy controls (HC), and (B) between RA patients with high L5% and normal L5%. (C) Representative histogram of the flow cytometric analysis of CD11c expression on THP-1 cells. (D) Bar graph showing the percent CD11c expression levels on THP-1 cells treated with different doses of L1 or L5 and fetal bovine serum (FBS)-treated control cells. Data are the mean ± SEM for three independent experiments. * p < 0.05.
Figure 3
Figure 3
Effects of L5 on the expression of cytokines in monocytes and macrophages. The differences in the mRNA expression levels are shown for IL-6 (A), IL-8 (B), and (C) tumor necrosis factor-α (TNF-α) in THP-1 cells (human monocytic cell line) treated with different doses of L1 and L5. The differences in the mRNA expression levels are shown for IL-6 (D), IL-8 (E), and (F) TNF-α in THP-1 cells-derived macrophages treated with different doses of L1 and L5. Data are the mean ± SEM for three independent experiments. * p < 0.05.
Figure 4
Figure 4
Proposed model for the potential role of L5 in RA-related atherogenesis. L5 induces the expression of CD11c, which is associated with vascular plaque formation [23,27] and is a marker for M1 macrophages that secrete proinflammatory cytokines [26]. L5 also upregulates the expression of inflammatory cytokines, interleukin (IL)-6 and IL-8, in both monocytes and macrophages. In addition, L5 induces LOX-1 expression and promotes foam cell formation by uptake of L5. The elevated levels of inflammatory cytokines and macrophage foam cell formation may contribute to vascular plaque formation in RA-related atherogenesis.
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