The impact of the PCSK-9/VLDL-Receptor axis on inflammatory cell polarization

Studies have shown that lipoproteins, such as LDL and VLDL, as well as its major protein component ApoE2 impact on macrophage polarization important in atherosclerosis. Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key regulator of lipoprotein receptor expression. The present study investigated the effect of the VLDL/VLDL-receptor (VLDL-R) axis on mononuclear cell polarization, as well as the role of PCSK9 and PCSK9 inhibitors (PCSK9i) within this network.

Human monocytic THP-1 cells and human monocyte-derived macrophages isolated from peripheral blood mononuclear cells (PBMC) were treated with either LPS/IFN-γ to induce a pro-inflammatory phenotype, or with IL-4/IL-13 to induce an anti-inflammatory phenotype. Cells were then subjected to further treatments by lipoproteins, PCSK9, PCSK9i and lipoprotein receptor blockers.

LPS/IFN-γ treatment promoted a pro-inflammatory state with an increased expression of pro-inflammatory mediators such as TNF-α, CD80 and IL-1β. VLDL co-treatment induced a switch of this pro-inflammatory phenotype to an anti-inflammatory phenotype. In pro-inflammatory cells, VLDL significantly decreased the expression of pro-inflammatory markers e.g., TNF-α, CD80, and IL-1β. These effects were eliminated by PCSK9 and restored by co-incubation with a specific anti-PCSK9 monoclonal antibody (PCSK9i). Migration assays demonstrated that pro-inflammatory cells displayed a significantly higher invasive capacity when compared to untreated cells or anti-inflammatory cells. Moreover, pro-inflammatory cell chemotaxis was significantly decreased by VLDL-mediated acquisition of the anti-inflammatory phenotype. PCSK9 significantly lessened this VLDL-mediated migration inhibition, which was reversed by the PCSK9i.

VLDL promotes mononuclear cell differentiation towards an anti-inflammatory phenotype. PCSK9, via its capacity to inhibit VLDL-R expression, reverses the VLDL-mediated anti-inflammatory action, thereby promoting a pro-inflammatory phenotype. Thus, PCSK9 targeting therapies may exert anti-inflammatory properties within the vessel wall.