Proprotein convertase subtilisin kexin 9 is associated with disease activity and is implicated in immune activation in systemic lupus erythematosus

• Low-density lipoprotein (LDL) levels are increased by proprotein convertase subtilisin kexin 9 (PCSK9) which targets the LDL receptor. We recently reported that PCSK9 ameliorates dendritic cell (DC) activation by oxidized LDL (OxLDL), which is abundant in atherosclerotic plaques and is also associated with cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). Here, we investigated 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. The effects of PCSK9 and its inhibition by silencing were studied. Results PCSK9 levels were non-significantly higher among SLE-patients compared to controls but significantly associated with SLE disease activity, as determined by the Systemic Lupus Activity Measure ( p = 0.020) or the SLE Disease Activity Index ( p = 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 but not after adjusting for age. OxLDL induced PCSK9 in DCs and DC maturation with increased expression of CD86 and HLA-DR. The effects were significantly stronger in DCs 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.

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