Article Text

PDF
Extended report
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
  1. Carolyne K Smith1,
  2. Nickie L Seto1,
  3. Anuradha Vivekanandan-Giri2,
  4. Wenmin Yuan3,
  5. Martin P Playford4,
  6. Zerai Manna5,
  7. Sarfaraz A Hasni5,
  8. Rui Kuai3,
  9. Nehal N Mehta4,
  10. Anna Schwendeman3,
  11. Subramaniam Pennathur2,
  12. Mariana J Kaplan1
  1. 1Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland, USA
  2. 2Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
  3. 3Department of Medicinal Chemistry, The Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Section of Inflammation and Cardiometabolic Diseases, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA
  5. 5Lupus Clinical Research Program, Office of the Clinical Director, NIAMS/NIH, Bethesda, Maryland, USA
  1. Correspondence to Dr Mariana J Kaplan, Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, 10 Center Dr., Room 6D47C; Bethesda MD 20892, USA; mariana.kaplan{at}nih.gov

Abstract

Objectives 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.

  • Systemic Lupus Erythematosus
  • Inflammation
  • Atherosclerosis
  • Cytokines
  • Lipids

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.