Lupus HDL Induces Pro-Inflammatory Responses in Macrophages By Binding LOX1Rand Failing to Promote ATF3 Activity

Carolyne K. Smith¹, Nickie Seto¹, Anuradha Vivekanandan-Giri², Wenmin Yuan³, Martin Playford⁴, Zerai G. Manna⁵, Sarfaraz A. Hasni⁶, Rui Kuai³, Nehal N. Mehta⁴, Anna Schwendeman³, Subramaniam Pennathur² and Mariana Kaplan⁷, ¹Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ²Internal Medicine/Nephrology, University of Michigan Nephrology, Ann Arbor, MI, ³Department of Medicinal Chemistry and the Biointerfaces Institute, University of Michigan, Ann Arbor, MI, ⁴NHLBI, National Institutes of Health, Bethesda, MD, ⁵National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, ⁶Lupus Clinical Research Program, Office of the Clinical Director, NIAMS/NIH, Bethesda, MD, ⁷NIAMS/NIH, Bethesda, MD

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Cardiovascular disease, inflammation and macrophages, Lupus

Session Information

Date: Tuesday, November 15, 2016

Title: Systemic Lupus Erythematosus – Human Etiology and Pathogenesis - Poster II

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: 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. Systemic lupus erythematosus (SLE) is associated with increased cardiovascular disease (CVD) risk not explained by the Framingham risk score. Recent studies have indicated oxidized 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 human macrophages were challenged with purified human control and SLE HDL in vitro in the presence or absence of TLR agonists and examined for induction of inflammatory markers by real time RT-PCR, confocal microscopy, ELISA and flow cytometry. The effect of an HDL mimetic (ETC-642) was examined in vivo in NZM2328 lupus-prone mice.

Results: Compared to 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. SLE HDL-induced pro-inflammatory responses in macrophages are dependent on its binding to lectin-like oxidized 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 ETC-642 show improved ATF3 induction and significant abrogation of pro-inflammatory responses.

Conclusion: Lupus HDL promotes pro-inflammatory responses through activation of NFκB and decreased ATF3 synthesis and activity, in a LOX1R- and ROCK1/2 kinase-dependent manner. HDL mimetics should be further explored as potential therapies to hamper inflammation and reduce cardiovascular risk in SLE.

Disclosure: C. K. Smith, None; N. Seto, None; A. Vivekanandan-Giri, None; W. Yuan, None; M. Playford, None; Z. G. Manna, None; S. A. Hasni, None; R. Kuai, None; N. N. Mehta, None; A. Schwendeman, None; S. Pennathur, None; M. Kaplan, None.

To cite this abstract in AMA style:

Smith CK, Seto N, Vivekanandan-Giri A, Yuan W, Playford M, Manna ZG, Hasni SA, Kuai R, Mehta NN, Schwendeman A, Pennathur S, Kaplan M. Lupus HDL Induces Pro-Inflammatory Responses in Macrophages By Binding LOX1Rand Failing to Promote ATF3 Activity [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/lupus-hdl-induces-pro-inflammatory-responses-in-macrophages-by-binding-lox1rand-failing-to-promote-atf3-activity/. Accessed .

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