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II-17 Lupus HDL promotes pro-inflammatory responses in macrophages through LOX1R binding and abrogation of ATF3 activity
  1. Carolyne K Smith1,
  2. Anuradha Vivekanandan-Giri2,
  3. Wenmin Yuan3,
  4. Martin P Playford4,
  5. Nehal Mehta4,
  6. Anna Schwendeman3,
  7. Subramaniam Pennathur2 and
  8. Mariana J Kaplan1
  1. 1Systemic Autoimmunity Branch, NIH, NIAMS
  2. 2Division of Nephrology, Department of Internal Medicine, University of Michigan
  3. 3Department of Medicinal Chemistry and the Biointerfaces Institute, University of Michigan
  4. 4Section of Inflammation and Cardiometabolic Diseases, NIH, NIHLBI

Abstract

Background Recent evidence indicates that high-density lipoprotein (HDL) exerts vasculoprotective activities by promoting activating transcription factor 3 (ATF3), leading to down-regulation of TLR-induced inflammatory responses. SLE is associated with increased cardiovascular disease (CVD) 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 and results Compared to control HDL, SLE HDL activates NFKB, 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. SLE HDL-induced pro-inflammatory responses in macrophages are dependent on its binding to lectin-like oxidised low-density lipoprotein receptor 1 (LOX1R), which promotes suppression of ATF3 activity in a ROCK1/2 kinase-dependent manner. This inflammation can be modulated in vivo as lupus-prone mice exposed to the HDL mimetic ETC-642 show improved ATF3 induction and significant abrogation of pro-inflammatory cytokines

Conclusions Lupus HDL promotes pro-inflammatory responses, increased NFκB activity and decreased ATF3 synthesis and activity, in a LOX1R- and ROCK1/2 kinase-dependent manner. ETC-642 inhibited both in vitro and in vivo SLE HDL-induced inflammation.

Acknowledgements Funded by Intramural Research Program at NIAMS and by Lupus Research Institute.

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