Lupus oxidized high density lipoprotein promotes macrophage inflammation by blocking ATF3 activity

FARE Award Winner

Authors

• CK Smith
• SM Gordon
• A Vivekanandan-Giri
• MP Playford
• N Mehta
• AT Remaley
• S Pennathur
• MJ Kaplan

Abstract

Abstract: Lupus (SLE) patients are fifty times more likely to experience a cardiovascular event compared to age- and sex-matched controls. High levels of oxidized HDL (oxHDL) in SLE patients may contribute to this association. Under normal conditions, unoxidized HDL induces an anti-inflammatory response within macrophages (MØ). We addressed whether lupus oxHDL modifies this response and putative mechanisms associated with enhanced inflammation. Methods: Healthy macrophages were incubated with HDL, isolated from healthy control, or SLE patients, prior to a TLR agonist challenge and examined for IL-6, IL-1β, IL-12B and TNFα production, as well as NFκB activation. The production and activity of the anti-inflammatory transcription factor ATF3 was examined following HDL incubation. Results: MØs exposed to SLE HDL up-regulate IL-6, IL-12B and TNF at the mRNA and protein levels, compared to MØs exposed to healthy HDL. SLE HDL showed impaired induction of ATF3 mRNA and nuclear translocation. ATF3 activity was restored when the oxHDL binding protein LOX-1 receptor was inhibited with blocking antibodies. Conclusion: Lupus HDL induces inflammatory responses in macrophages which may promote phenotypic proatherogenic changes and increase cardiovascular risk in this disease. Modifying the HDL proteome in SLE may decrease this risk.

Scientific Focus Area: Immunology

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