PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque.

BACKGROUND

Activated T cells and dendritic cells (DCs) occur in atherosclerotic plaques. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL-receptor (LDLR) and results in increased LDL levels. We here investigate immune effects of PCSK9 on OxLDL induced DC maturation and T-cell activation.

METHODS

T cells were isolated from carotid specimens of patients undergoing carotid endarterectomy or from peripheral blood of healthy individuals. Human peripheral blood monocytes were differentiated into DCs. Naïve T cells were cocultured with pretreated DCs. The effects of PCSK9 and its inhibition by silencing were studied.

RESULTS

OxLDL induced PCSK9 in DCs and promoted DC maturation with increased expressions of CD80, CD83, CD86 and HLA-DR and the scavenger receptors LOX-1 and CD36. T cells exposed to OxLDL-treated DCs proliferated and produced IFN-γ and IL-17, thus with polarization to Th1 and/or Th17 subsets. Silencing of PCSK9 reversed the OxLDL effects on DCs and T cells. DC maturation was repressed, and the production of TNF-α, IL-1β and IL-6 was limited, while TGF-β and IL-10 secretion and T regulatory cells were induced. OxLDL induced miRNA let-7c, miR-27a, miR-27b, miR-185. Silencing PCSK9 repressed miR-27a and to a lesser extent let-7c. PCSK9 silencing enhanced SOCS1 expression induced by OxLDL. Experiments on T cells from carotid atherosclerotic plaques or healthy individuals showed similar results.

CONCLUSIONS

We demonstrate immunological effects of PCSK9 in relation to activation and maturation of DCs and plaque T cells by OxLDL, a central player in atherosclerosis. This may directly influence atherosclerosis and cardiovascular disease, independent of LDL lowering.