title: Lupus high-density lipoprotein induces proinflammatory responses in macrophages by binding lectin-like oxidised low-density lipoprotein receptor 1 and failing to promote activating transcription factor 3 activity.
abstract: OBJECTIVE
  Recent evidence indicates that high-density lipoprotein (HDL) exerts vasculoprotective activities by promoting activating transcription factor 3 (ATF3), leading to downregulation of toll-like receptor (TLR)-induced inflammatory responses. Systemic lupus erythematosus (SLE) is associated with increased cardiovascular disease risk not explained by the Framingham risk score. Recent studies have indicated oxidised HDL as a possible contributor. We investigated the potential mechanisms by which lupus HDL may lose its anti-inflammatory effects and promote immune dysregulation.
  
  
  METHODS
  Control macrophages were challenged with control and SLE HDL in vitro and examined for inflammatory markers by real-time qRT-PCR, confocal microscopy, ELISA and flow cytometry. Lupus-prone mice were treated with an HDL mimetic (ETC-642) in vivo and inflammatory cytokine levels measured by real-time qRT-PCR and ELISA.
  
  
  RESULTS
  Compared with control HDL, SLE HDL activates NFκB, promotes inflammatory cytokine production and fails to block TLR-induced inflammation in control macrophages. This failure of lupus HDL to block inflammatory responses is due to an impaired ability to promote ATF3 synthesis and nuclear translocation. This inflammation is dependent on lectin-like oxidised low-density lipoprotein receptor 1 (LOX1R) binding and rho-associated, coiled-coil containing protein kinase 1 and 2 (ROCK1/2) kinase activity. HDL mimetic-treated lupus mice showed significant ATF3 induction and proinflammatory cytokine abrogation.
  
  
  CONCLUSIONS
  Lupus HDL promotes proinflammatory responses through NFκB activation and decreased ATF3 synthesis and activity in an LOX1R-dependent and ROCK1/2-dependent manner. HDL mimetics should be explored as potential therapies for inflammation and SLE cardiovascular risk.
authors.affiliation: Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Carolyne K
authors.initials: CK
authors.lastname: Smith
authors.affiliation: Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Nickie L
authors.initials: NL
authors.lastname: Seto
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Vivekanandan-Giri
authors.affiliation: Department of Medicinal Chemistry, The Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Wenmin
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Martin P
authors.initials: MP
authors.lastname: Playford
authors.affiliation: Lupus Clinical Research Program, Office of the Clinical Director, NIAMS/NIH, Bethesda, Maryland, USA.
authors.forename: Zerai
authors.initials: Z
authors.lastname: Manna
authors.affiliation: Lupus Clinical Research Program, Office of the Clinical Director, NIAMS/NIH, Bethesda, Maryland, USA.
authors.forename: Sarfaraz A
authors.initials: SA
authors.lastname: Hasni
authors.affiliation: Department of Medicinal Chemistry, The Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Kuai
authors.affiliation: Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Nehal N
authors.initials: NN
authors.lastname: Mehta
authors.affiliation: Department of Medicinal Chemistry, The Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Schwendeman
authors.affiliation: Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
authors.affiliation: Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000494:pharmacology; D051700:Activating Transcription Factor 3 / Q000096:biosynthesis* / Q000378:metabolism; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000577:Amides / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics*; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism* / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood*; D008264:Macrophages; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010455:Peptides / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D051117:Scavenger Receptors, Class A / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology; D051193:Toll-Like Receptors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D000577:Amides; C103002:Atf3 protein, mouse; D016207:Cytokines; C568357:ETC 642; D008075:Lipoproteins, HDL; D016328:NF-kappa B; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; D013109:Sphingomyelins; D051193:Toll-Like Receptors; C108830:Y 27632; D015060:1,2-Dipalmitoylphosphatidylcholine; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases
keywords: Atherosclerosis; Cytokines; Inflammation; Lipids; Systemic Lupus Erythematosus