Abstract
Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 µg/ml PCSK9, a significant induction of IL-1β, IL-6, TNF-α, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-α (2.4 ± 0.5 fold) and IL-1β (8.6 ± 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-α mRNA in murine LDLR−/− bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 ± 1.6 fold vs 31.1 ± 6.1 fold for LDLR−/− and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-α plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 ÷ 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR.
Highlights
Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs)
We demonstrated that recombinant human Proprotein convertase subtilisin kexin type 9 (PCSK9) induced a pro-inflammatory phenotype, by increasing the expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines (Monocyte Chemotactic Protein 1, MCP1 and Chemokine C-X-C motif ligand 2, CXCL2) in human THP1 and primary macrophages, as well as in bone marrow derived macrophages (BMM)
To test the hypothesis that PCSK9 could have a pro-inflammatory effect on macrophages, we first performed a series of experiments with macrophages derived from human monocyte cell line THP-1 incubated with increasing concentrations of human recombinant PCSK9
Summary
Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). The present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR. The study of the central role of macrophages in atherogenesis led to the observation of the presence of two different macrophage populations that can be grossly divided into pro-inflammatory (M1 cells) and anti-inflammatory (M2 cells) based mainly on in vitro criteria[3]. Among the different mechanisms that have been postulated, one points toward the increase of plasma membrane cholesterol through the involvement of the TLRs4,5 Despite this evidence, a number of studies show opposite results, such as an anti-inflammatory phenotype induced by intracellular cholesterol[6]
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