PCSK9 induces a pro-inflammatory response in macrophages

Area of Science:

• Cardiovascular Biology
• Immunology
• Molecular Medicine

Background:

• Macrophage-derived inflammatory cytokines contribute to atherogenesis by promoting smooth muscle cell proliferation and migration.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) is found in atherosclerotic plaques, but its role in inflammation is unclear.

Purpose of the Study:

• To investigate the potential pro-inflammatory effects of PCSK9 on macrophages.
• To determine the role of the low-density lipoprotein receptor (LDLR) in PCSK9-mediated macrophage inflammation.

Main Methods:

• Human THP-1-derived and primary macrophages were treated with recombinant human PCSK9 (hPCSK9).
• Co-culture experiments involved HepG2 cells overexpressing hPCSK9 and THP-1 macrophages.
• Murine bone marrow-derived macrophages (BMM) from wild-type and LDLR knockout mice were used.
• Plasma levels of PCSK9 and TNF-α were measured in healthy adults.

Main Results:

• hPCSK9 treatment significantly induced mRNA expression of inflammatory cytokines (IL-1β, IL-6, TNF-α, CXCL2, MCP1) in macrophages.
• Co-culture with PCSK9-overexpressing cells increased TNF-α and IL-1β mRNA in macrophages.
• The pro-inflammatory effect of hPCSK9 on TNF-α mRNA was significantly reduced in LDLR knockout macrophages compared to wild-type.
• A positive correlation was observed between plasma PCSK9 and TNF-α levels in healthy individuals.

Conclusions:

• PCSK9 exerts a pro-inflammatory effect on macrophages, stimulating the release of key inflammatory cytokines.
• The low-density lipoprotein receptor (LDLR) plays a crucial role in mediating PCSK9's pro-inflammatory actions on macrophages.
• These findings suggest PCSK9 may contribute to inflammatory processes in atherosclerosis.