PCSK9 induces a pro-inflammatory response in macrophages

Chiara Ricci, Massimiliano Ruscica, Marina Camera, Laura Rossetti, Chiara Macchi, Alessandra Colciago, Ilaria Zanotti, Maria Giovanna Lupo, Maria Pia Adorni, Arrigo F G Cicero, Federica Fogacci, Alberto Corsini, Nicola Ferri

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2267
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Feb 2 2018

Fingerprint

Macrophages
Interleukin-1
Messenger RNA
Smooth Muscle Myocytes
Bone Marrow
Atherosclerotic Plaques
Coculture Techniques
Interleukin-6
Atherosclerosis
Healthy Volunteers
Cytokines

Keywords

  • Animals
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines/metabolism
  • Female
  • Humans
  • Macrophages/immunology
  • Male
  • Mice
  • Proprotein Convertase 9/metabolism

Cite this

PCSK9 induces a pro-inflammatory response in macrophages. / Ricci, Chiara; Ruscica, Massimiliano; Camera, Marina; Rossetti, Laura; Macchi, Chiara; Colciago, Alessandra; Zanotti, Ilaria; Lupo, Maria Giovanna; Adorni, Maria Pia; Cicero, Arrigo F G; Fogacci, Federica; Corsini, Alberto; Ferri, Nicola.

In: Scientific Reports, Vol. 8, No. 1, 02.02.2018, p. 2267.

Research output: Contribution to journalArticle

Ricci, C, Ruscica, M, Camera, M, Rossetti, L, Macchi, C, Colciago, A, Zanotti, I, Lupo, MG, Adorni, MP, Cicero, AFG, Fogacci, F, Corsini, A & Ferri, N 2018, 'PCSK9 induces a pro-inflammatory response in macrophages', Scientific Reports, vol. 8, no. 1, pp. 2267. https://doi.org/10.1038/s41598-018-20425-x
Ricci, Chiara ; Ruscica, Massimiliano ; Camera, Marina ; Rossetti, Laura ; Macchi, Chiara ; Colciago, Alessandra ; Zanotti, Ilaria ; Lupo, Maria Giovanna ; Adorni, Maria Pia ; Cicero, Arrigo F G ; Fogacci, Federica ; Corsini, Alberto ; Ferri, Nicola. / PCSK9 induces a pro-inflammatory response in macrophages. In: Scientific Reports. 2018 ; Vol. 8, No. 1. pp. 2267.
@article{c5b6428df6f048c8a2c6e218a5905322,
title = "PCSK9 induces a pro-inflammatory response in macrophages",
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.",
keywords = "Animals, Cells, Cultured, Coculture Techniques, Cytokines/metabolism, Female, Humans, Macrophages/immunology, Male, Mice, Proprotein Convertase 9/metabolism",
author = "Chiara Ricci and Massimiliano Ruscica and Marina Camera and Laura Rossetti and Chiara Macchi and Alessandra Colciago and Ilaria Zanotti and Lupo, {Maria Giovanna} and Adorni, {Maria Pia} and Cicero, {Arrigo F G} and Federica Fogacci and Alberto Corsini and Nicola Ferri",
year = "2018",
month = "2",
day = "2",
doi = "10.1038/s41598-018-20425-x",
language = "English",
volume = "8",
pages = "2267",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - PCSK9 induces a pro-inflammatory response in macrophages

AU - Ricci, Chiara

AU - Ruscica, Massimiliano

AU - Camera, Marina

AU - Rossetti, Laura

AU - Macchi, Chiara

AU - Colciago, Alessandra

AU - Zanotti, Ilaria

AU - Lupo, Maria Giovanna

AU - Adorni, Maria Pia

AU - Cicero, Arrigo F G

AU - Fogacci, Federica

AU - Corsini, Alberto

AU - Ferri, Nicola

PY - 2018/2/2

Y1 - 2018/2/2

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Coculture Techniques

KW - Cytokines/metabolism

KW - Female

KW - Humans

KW - Macrophages/immunology

KW - Male

KW - Mice

KW - Proprotein Convertase 9/metabolism

U2 - 10.1038/s41598-018-20425-x

DO - 10.1038/s41598-018-20425-x

M3 - Article

C2 - 29396513

VL - 8

SP - 2267

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

ER -