Abstract

Abstract Background The risk of atherosclerosis and cardiovascular disease (CVD) is very high in SLE. This is both a clinical problem and of interest in studies of immunity in these conditions. LDL-levels are increased by Proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL-receptor (LDLR). We recently reported that PCSK9 ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL), which is abundant in atherosclerotic plaques and also raised and associated with cardiovascular disease (CVD) in SLE. We here investigate the role of PCSK9 in SLE. Methods PCSK9-levels were determined by ELISA among SLE patients (n=109) and age- and sex-matched population-based controls (n=91). Common carotid intima-media thickness (IMT) and plaque occurrence were determined by B-mode ultrasound. Plaques were graded by echogenicity. Human peripheral blood monocytes from SLE patients or controls were differentiated into DCs. Effects of PCSK9 and its inhibition by silencing were studied. Results PCSK9-levels were non-significantly higher among SLE-patients as compared to controls but associated significantly with SLE disease activity, as determined by SLAM (0.020) or SLEDAI (0.0178). There was no association between PCSK9-levels and atherosclerosis as determined by IMT, prevalence of plaques or echolucent (potentially vulnerable) plaques. PCSK9 levels were significantly associated with CVD among SLE-patients. OxLDL induced PCSK9 in DCs and DC-maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DC from SLE patients than from controls. Silencing of PCSK9 abolished OxLDL-induced DC-maturation. Conclusions PCSK9 is associated with disease activity in SLE. One underlying cause could be OxLDL, promoting DC-activation which depends on PCSK9. OxLDL induces PCSK9, an effect which is higher among SLE-patients. PCSK9 could play an unexpected immunological role in SLE. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Amgen; Swedish Heart and Lung Foundation

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