High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling

doi:10.1016/j.cmet.2016.10.013

. 2017 Jan 10;25(1):197-207.

doi: 10.1016/j.cmet.2016.10.013. Epub 2016 Nov 17.

High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling

Emiel P C van der Vorst¹, Kosta Theodorou², Yongzheng Wu³, Marten A Hoeksema⁴, Pieter Goossens⁵, Christina A Bursill⁶, Taghi Aliyev⁷, Leonie F A Huitema⁸, Sander W Tas⁸, Ine M J Wolfs², Marijke J E Kuijpers⁹, Marion J Gijbels¹⁰, Casper G Schalkwijk¹¹, Debby P Y Koonen¹², Shahla Abdollahi-Roodsaz¹³, Kimberly McDaniels¹⁴, Chih-Chieh Wang¹⁴, Michael Leitges¹⁵, Toby Lawrence⁵, Jogchum Plat¹⁶, Miranda Van Eck¹⁷, Kerry-Anne Rye¹⁸, Lhousseine Touqui¹⁹, Menno P J de Winther⁴, Erik A L Biessen²⁰, Marjo M P C Donners²¹

Affiliations

¹ Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336 Munich, Germany. Electronic address: e.vandervorst@maastrichtuniversity.nl.
² Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
³ Unit of Cellular Biology of Microbial Infection, CNRS UMR3691, Institut Pasteur, 75015 Paris, France.
⁴ Department of Medical Biochemistry, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁵ Inflammation Biology Group, Centre d'Immunologie Marseille-Luminy, 13288 Marseille, France.
⁶ Heart Research Institute, 2050 Newtown, Australia; Sydney Medical School, University of Sydney, 2006 Sydney, Australia.
⁷ Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
⁸ Amsterdam Rheumatology and Immunology Center, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁹ Department of Biochemistry, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
¹⁰ Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Medical Biochemistry, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
¹¹ Department of Internal Medicine, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
¹² Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
¹³ Department of Experimental Rheumatology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, the Netherlands.
¹⁴ Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Biotechnology Centre of Oslo, University of Oslo, 0313 Oslo, Norway.
¹⁶ Department of Human Biology, Nutrim, Maastricht University, 6200 MD Maastricht, the Netherlands.
¹⁷ Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
¹⁸ Heart Research Institute, 2050 Newtown, Australia; Sydney Medical School, University of Sydney, 2006 Sydney, Australia; Centre for Vascular Research, University of New South Wales, 2052 Sydney, Australia.
¹⁹ Department of Infection & Epidemiology, Institut Pasteur, 75015 Paris, France.
²⁰ Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; IMCARIM, Uniklinikum Aachen, 52074 Aachen, Germany.
²¹ Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands. Electronic address: marjo.donners@maastrichtuniversity.nl.

PMID: 27866837
DOI: 10.1016/j.cmet.2016.10.013

Free article

High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling

Emiel P C van der Vorst et al. Cell Metab. 2017.

Free article

. 2017 Jan 10;25(1):197-207.

doi: 10.1016/j.cmet.2016.10.013. Epub 2016 Nov 17.

Authors

Affiliations

¹ Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, 80336 Munich, Germany. Electronic address: e.vandervorst@maastrichtuniversity.nl.
² Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
³ Unit of Cellular Biology of Microbial Infection, CNRS UMR3691, Institut Pasteur, 75015 Paris, France.
⁴ Department of Medical Biochemistry, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁵ Inflammation Biology Group, Centre d'Immunologie Marseille-Luminy, 13288 Marseille, France.
⁶ Heart Research Institute, 2050 Newtown, Australia; Sydney Medical School, University of Sydney, 2006 Sydney, Australia.
⁷ Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
⁸ Amsterdam Rheumatology and Immunology Center, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
⁹ Department of Biochemistry, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
¹⁰ Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Medical Biochemistry, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
¹¹ Department of Internal Medicine, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
¹² Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
¹³ Department of Experimental Rheumatology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, the Netherlands.
¹⁴ Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Biotechnology Centre of Oslo, University of Oslo, 0313 Oslo, Norway.
¹⁶ Department of Human Biology, Nutrim, Maastricht University, 6200 MD Maastricht, the Netherlands.
¹⁷ Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
¹⁸ Heart Research Institute, 2050 Newtown, Australia; Sydney Medical School, University of Sydney, 2006 Sydney, Australia; Centre for Vascular Research, University of New South Wales, 2052 Sydney, Australia.
¹⁹ Department of Infection & Epidemiology, Institut Pasteur, 75015 Paris, France.
²⁰ Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; IMCARIM, Uniklinikum Aachen, 52074 Aachen, Germany.
²¹ Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands. Electronic address: marjo.donners@maastrichtuniversity.nl.

PMID: 27866837
DOI: 10.1016/j.cmet.2016.10.013

Abstract

Membrane cholesterol modulates a variety of cell signaling pathways and functions. While cholesterol depletion by high-density lipoproteins (HDLs) has potent anti-inflammatory effects in various cell types, its effects on inflammatory responses in macrophages remain elusive. Here we show overt pro-inflammatory effects of HDL-mediated passive cholesterol depletion and lipid raft disruption in murine and human primary macrophages in vitro. These pro-inflammatory effects were confirmed in vivo in peritoneal macrophages from apoA-I transgenic mice, which have elevated HDL levels. In line with these findings, the innate immune responses required for clearance of P. aeruginosa bacterial infection in lung were compromised in mice with low HDL levels. Expression analysis, ChIP-PCR, and combinatorial pharmacological and genetic intervention studies unveiled that both native and reconstituted HDL enhance Toll-like-receptor-induced signaling by activating a PKC-NF-κB/STAT1-IRF1 axis, leading to increased inflammatory cytokine expression. HDL's pro-inflammatory activity supports proper functioning of macrophage immune responses.

Keywords: bacterial infection; high-density lipoproteins; immune response; inflammation; inflammatory signaling; macrophages; passive cholesterol depletion.

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High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling

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High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling

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