Systemic lupus erythematosus aggravates atherosclerosis by promoting IgG deposition and inflammatory cell imbalance

Abstract

Background: Systemic lupus erythematosus (SLE) patients experience a premature and more severe presentation of coronary artery disease. The underlying mechanisms of accelerated coronary artery disease in SLE patients remain to be elucidated.

Methods: By using atherosclerosis combining a SLE murine model, we proved that the onset of SLE aggravates atherosclerosis. Although the onset of SLE reduced blood lipids slightly, immune deviation contributed to aggravated atherosclerosis in lupus mice. Lupus atheroma were characterized by inflammatory cell infiltration, such as gathered dendritic cells, macrophages, and IgG deposition.

Results: Decreased lymphocytes and magnified dendritic cells in the spleen were also observed in lupus mice. Hydroxychloroquine prevented atherosclerosis progression mainly by reversing immune status abnormality caused by SLE. Serum interferon alfa levels were not changed in lupus mice.

Conclusion: These findings strongly suggested that anti-inflammatory therapies and hydroxychloroquine provide a new possible strategy for treating SLE patients with atherosclerosis.

Keywords: IgG; Systemic lupus erythematosus (SLE); atherosclerosis; blood lipids; hydroxychloroquine.

Figure 1

dsDNA antibodies and skin lesions. (a) dsDNA antibodies in mice sera 6 months after pristane or phosphate-buffered saline (PBS) injection. (b) PBS-injected mice had no skin lesions. (c) Alopecia and skin haemorrhage of lupus mice. HCQ: hydroxychloroquine. *P < 0.05, **P < 0.01.

Figure 2

Aorta Oil Red O staining. (a) Oil Red O staining of aorta. (b) Percentage of Oil Red O staining positive area in aorta. (c) Oil Red O staining of aortic sinus section. (d) Percentage of Oil Red O staining positive area in aortic sinus section. (e)–(h) Effect of HCQ on aorta Oil Red O staining. (e) Oil Red O staining of aorta. (f) Percentage of Oil Red O staining positive area in aorta. (g) Oil Red O staining of aortic sinus section. (h) Percentage of Oil Red O staining positive area in aortic sinus section. HFD: high fat diet fed; CD: chow diet fed; HCQ: hydroxychloroquine.

Figure 3

Serum lipid level. (a) Serum total cholesterol (TC) level. (b) Serum low-density lipoprotein (LDL) cholesterol. Lupus mice had lower serum TC level and LDL-cholesterol level compared to non-lupus mice. *P < 0.05.

Figure 4

Inflammatory cells in aortas. (a) Aortic leukocytes increased significantly in lupus mice. Aortic leukocytes decreased in lupus mice when hydroxychloroquine was administered. (b)–(d) Onset of lupus increased inflammatory cells in aortas, while hydroxychloroquine administration reduced aortic inflammatory cells. (b) Flow cytometry analysis of CD68⁺ and CD11c⁺ cells. (c) Aortic CD45⁺CD68⁺ cell numbers. (d) Aortic CD45⁺CD11c⁺ cell numbers. (e)–(f) Macrophages and dendritic cells are highly correlated. (e) Correlation analysis of CD68⁺ cell number and CD11c⁺ cell number. (f) Immunofluorescence staining of CD68⁺ and CD11c⁺ cells.

Figure 5

Extra IgG deposition within plaques was observed in lupus mice, while hydroxychloroquine treatment reduced IgG deposition in plaques. (a) and (c) Immunofluorescence staining of IgG in aortic sinus in ApoE^–/– mice. (b) Oil Red O staining compared to IgG staining. (d) IgG deposition area in aortic sinus cross-section. (e) Serum IgG elevated in lupus mice. (f) Serum IgG and IgG deposition were not correlated.

Figure 6

Serum interferon alfa (IFN-α) level. No significant serum IFN-α level change was detected.