Modulation of macrophage responses by aberrant lipoproteins in chronic inflammatory diseases. (HUM3P.241)

• Published in: The Journal of immunology (1950) 2015-05, Vol.194 (1_Supplement), p.121-121.1
• Main Authors: Smith, Carolyne, Vivekanandan-Giri, Anuradha, Playford, Martin, Berthier, Celine, Kretzler, Matthias, Mehta, Nehal, Pennathur, Subramaniam, Kaplan, Mariana
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.194.Supp.121.1

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: Affymetrix gene expression analysis was performed on control MØs exposed to control or lupus HDL before an LPS challenge. Confirmation at the mRNA and protein level was performed. Signaling pathways involved in gene induction abnormalities were explored using molecular approaches. Results: MØs exposed to SLE HDL up-regulate IL-6, IL-12B and TNF-α 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. SLE HDL also showed a decrease activation of kinases upstream of ATF3 activation. 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.