The Interplay of Lipoproteins and Innate Immune Responses in Systemic Lupus Erythematosus and its Role in Premature Cardiovascular Disease.

Innate Immune Mechanisms in Lupus-associated Cardiovascular Disease;Microbiology and Immunology;Health Sciences;Immunology

Smith, Carolyne K.Pennathur, Subramaniam ;

University of Michigan

关键词: Innate Immune Mechanisms in Lupus-associated Cardiovascular Disease;    Microbiology and Immunology;    Health Sciences;    Immunology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/116769/cksm_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Systemic lupus erythematosus (SLE) is an autoimmune syndrome that primarily affects women and leads to significant internal organ damage. Patients with SLE exhibit a high risk for premature atherosclerotic cardiovascular disease (CVD) not associated with traditional risk factors. It is therefore necessary to establish specific biomarkers for CVD risk in SLE patients and to further elucidate the interplay between the aberrant innate immune system and lipoprotein biology present in SLE atherosclerosis. Recent evidence links oxidized high-density lipoprotein (oxHDL) with accelerated ;;typical” CVD. It remains to be determined whether these modifications also occur in SLE, which mechanisms lead to this modification, and what impact oxHDL has on SLE CVD innate immune responses. We hypothesized that the chronic oxidative environment in SLE promotes pro-atherogenic alterations to HDL. We further posited that neutrophil extracellular trap (NET) formation, which is enhanced in SLE, significantly contributes to HDL oxidation. Finally, we predicted that SLE HDL skews macrophages toward pro-inflammatory and pro-atherosclerotic pathways. We demonstrated that lupus patients had high levels of oxHDL and impaired HDL-associated vasoprotective activity. We found that the oxidative machinery externalized in NETs induces HDL oxidation. Indeed, when we suppressed NETosis in lupus-prone mice in vivo, levels of oxHDL significantly decreased. When healthy macrophages were exposed to this SLE HDL, they displayed high levels of inflammation. While healthy HDL blocked toll-like receptor (TLR)-induced inflammatory cytokine production, SLE HDL failed to abrogate this inflammation. This was linked to an impaired ability of SLE HDL to promote the transcriptional repressor activating transcription factor 3 (ATF3). These SLE HDL-induced effects were largely dependent on its binding the lectin-like oxidized low-density lipoprotein receptor (LOX1R). Finally, administration of an HDL mimetic to lupus-prone mice, in vivo, decreased their inflammatory cytokine profile and enhanced ATF3 mRNA levels.These studies identify a specific oxidation pattern that could be used as a SLE CVD biomarker, as well as the potential therapeutic benefits of altering NET and lipoprotein activity in lupus. Additionally, we showed two innate immune response pathways that may contribute to SLE CVD. NET-derived oxidative species induce HDL oxidation. This oxHDL, in turn, stimulates pro-inflammatory, pro-atherogenic responses in macrophages.