The Impact of the PCSK-9 / VLDL-Receptor Axis on Inflammatory Cell Polarization

Background: Studies have shown that lipoproteins, including LDL, VLDL, and ApoE2 have an impact on macrophage polarization, important to atherosclerosis progression. PCSK9 is a key mediator regulating the expression of lipoprotein receptors. The present study investigates the effect of the VLDL/VLDL-R axis on mononuclear cell polarization, as well as the role of PCSK9 and PCSK9 inhibitors (PCSK9i) within this network.Methods: Human monocytic THP-1 cells and human monocyte-derived macrophages isolated from PBMC were treated with 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 including VLDL, LDL, PCSK9, PCSK9i, anti-LDL-R; PMA and TSP-1.Results: LPS/IFN-γ treatment promoted a pro-inflammatory state with an increased expression of pro-inflammatory mediators e.g., 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 the M1-markers e.g., TNF-α, CD80, and IL-1β. These effects were eliminated by PCSK9 and restored by co-incubation with a PCSK9i. Migration assays demonstrated that pro-inflammatory cells displayed a significantly higher invasive capacity 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.Conclusion: VLDL promotes macrophage differentiation towards the anti-inflammatory phenotype. PCSK9, via its capacity to inhibit VLDL-R expression, reverses the VLDL-mediated anti-inflammatory switch, thereby promoting a pro-inflammatory phenotype. Thus, anti-PCSK9 therapies may exert pro-inflammatory suppression within the vessel wall.