Abstract
Aims: Anti-Apolipoprotein A-1 autoantibodies (anti-ApoA-1 IgG) promote atherogenesis via innate immune receptors, and may impair cellular cholesterol homeostasis (CH). We explored the presence of anti-ApoA-1 IgG in children (5–15 years old) with or without familial hypercholesterolemia (FH), analyzing their association with lipid profiles, and studied their in vitro effects on foam cell formation, gene regulation, and their functional impact on cholesterol passive diffusion (PD). Methods: Anti-ApoA-1 IgG and lipid profiles were measured on 29 FH and 25 healthy children. The impact of anti-ApoA-1 IgG on key CH regulators (SREBP2, HMGCR, LDL-R, ABCA1, and miR-33a) and foam cell formation detected by Oil Red O staining were assessed using human monocyte-derived macrophages. PD experiments were performed using a validated THP-1 macrophage model. Results: Prevalence of high anti-ApoA-1 IgG levels (seropositivity) was about 38% in both study groups. FH children seropositive for anti-ApoA-1 IgG had significant lower total cholesterol LDL and miR-33a levels than those who were seronegative. On macrophages, anti-ApoA-1 IgG induced foam cell formation in a toll-like receptor (TLR) 2/4-dependent manner, accompanied by NF-kB- and AP1-dependent increases of SREBP-2, LDL-R, and HMGCR. Despite increased ABCA1 and decreased mature miR-33a expression, the increased ACAT activity decreased membrane free cholesterol, functionally culminating to PD inhibition. Conclusions: Anti-ApoA-1 IgG seropositivity is frequent in children, unrelated to FH, and paradoxically associated with a favorable lipid profile. In vitro, anti-ApoA-1 IgG induced foam cell formation through a complex interplay between innate immune receptors and key cholesterol homeostasis regulators, functionally impairing the PD cholesterol efflux capacity of macrophages.
Highlights
Humoral autoimmunity has recently been shown to represent a dual mediator of atherogenesis and cardiovascular diseases (CVD) by modulating three main pathways, including inflammation, coagulation, and foam cell formation [1,2]
This clinical observation derived from a limited number of pediatric familial hypercholesterolemia (FH) patients, prompted us to evaluate the ability of anti-ApoA-1 IgG to promote in vitro foam cell development on human primary macrophages, and to determine the molecular mechanisms involved, which led to the following new mechanistic findings
If the role of the TLR2/4/CD14 complex has been well documented accounting for the cytokinedependent pro-inflammatory, pro-thrombotic, and pro-arrythmogenic biological properties ascribed to anti-ApoA-1 IgG [9,14,17], this is the first demonstration that these antibodies promote foam cell formation on human macrophages by the same innate immune receptors
Summary
Humoral autoimmunity has recently been shown to represent a dual mediator of atherogenesis and cardiovascular diseases (CVD) by modulating three main pathways, including inflammation, coagulation, and foam cell formation [1,2]. Since foam cells can be generated by the uncontrolled uptake of unmodified LDL via LDL-R [28,29], any factor influencing LDLR, HMGCR, or miR-33a expression will efficiently modulate lipid uptake, cellular cholesterol synthesis, and cholesterol efflux, and affect atherogenesis Taken together, these observations suggest that anti-ApoA-1 IgG may reorient the lipids from the plasmatic compartment toward the intracellular lipid pools, potentially explaining the paradoxical associations frequently retrieved between anti-apoA-1 IgG and lipid profile despite an increased CV risk. If so, such a hypothesis would imply modulation of key regulators of cellular cholesterol homeostasis and foam cell formation, including miR-33 In this translational study, we explored the associations between anti-ApoA-1 IgG, lipid profile, and miR-33a levels in FH children as an extreme and optimal human dyslipidemia phenotype to perform such explorations and compared whether such associations could be retrieved in age- and gender-matched controls. Our in vitro studies using human macrophages provided the first molecular insights on how these antibodies could act as novel endogenous cholesterol homeostasis disruptors
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