title: High-Density Lipoproteins Exert Pro-inflammatory Effects on Macrophages via Passive Cholesterol Depletion and PKC-NF-κB/STAT1-IRF1 Signaling.
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.
authors.affiliation: 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.
authors.forename: Emiel P C
authors.initials: EPC
authors.lastname: van der Vorst
authors.affiliation: Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Kosta
authors.initials: K
authors.lastname: Theodorou
authors.affiliation: Unit of Cellular Biology of Microbial Infection, CNRS UMR3691, Institut Pasteur, 75015 Paris, France.
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Marten A
authors.initials: MA
authors.lastname: Hoeksema
authors.affiliation: Inflammation Biology Group, Centre d'Immunologie Marseille-Luminy, 13288 Marseille, France.
authors.forename: Pieter
authors.initials: P
authors.lastname: Goossens
authors.affiliation: Heart Research Institute, 2050 Newtown, Australia; Sydney Medical School, University of Sydney, 2006 Sydney, Australia.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Bursill
authors.affiliation: Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Taghi
authors.initials: T
authors.lastname: Aliyev
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Leonie F A
authors.initials: LFA
authors.lastname: Huitema
authors.affiliation: Amsterdam Rheumatology and Immunology Center, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Sander W
authors.initials: SW
authors.lastname: Tas
authors.affiliation: Department of Molecular Genetics, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Ine M J
authors.initials: IMJ
authors.lastname: Wolfs
authors.affiliation: Department of Biochemistry, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Marijke J E
authors.initials: MJE
authors.lastname: Kuijpers
authors.affiliation: 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.
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Gijbels
authors.affiliation: Department of Internal Medicine, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands.
authors.forename: Debby P Y
authors.initials: DPY
authors.lastname: Koonen
authors.affiliation: Department of Experimental Rheumatology, Radboud University Nijmegen Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Shahla
authors.initials: S
authors.lastname: Abdollahi-Roodsaz
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: McDaniels
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Biotechnology Centre of Oslo, University of Oslo, 0313 Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: Inflammation Biology Group, Centre d'Immunologie Marseille-Luminy, 13288 Marseille, France.
authors.forename: Toby
authors.initials: T
authors.lastname: Lawrence
authors.affiliation: Department of Human Biology, Nutrim, Maastricht University, 6200 MD Maastricht, the Netherlands.
authors.forename: Jogchum
authors.initials: J
authors.lastname: Plat
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, Leiden University, 2333 CC Leiden, the Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.affiliation: 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.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.affiliation: Department of Infection & Epidemiology, Institut Pasteur, 75015 Paris, France.
authors.forename: Lhousseine
authors.initials: L
authors.lastname: Touqui
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Menno P J
authors.initials: MPJ
authors.lastname: de Winther
authors.affiliation: Department of Pathology, CARIM, Maastricht University, 6200 MD Maastricht, the Netherlands; IMCARIM, Uniklinikum Aachen, 52074 Aachen, Germany.
authors.forename: Erik A L
authors.initials: EAL
authors.lastname: Biessen
authors.affiliation: 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.
authors.forename: Marjo M P C
authors.initials: MMPC
authors.lastname: Donners
mesh_terms: D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology*; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D021962:Membrane Microdomains / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012141:Respiratory Tract Infections / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D050856:Interferon Regulatory Factor-1; D008075:Lipoproteins, HDL; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D051193:Toll-Like Receptors; D002784:Cholesterol; D011493:Protein Kinase C
keywords: bacterial infection; high-density lipoproteins; immune response; inflammation; inflammatory signaling; macrophages; passive cholesterol depletion