Anti-apolipoprotein A-1 IgG in patients with myocardial infarction promotes inflammation through TLR2/CD14 complex

作者：Pagano S^*; Satta N; Werling D; Offord V; de Moerloose P; Charbonney E; Hochstrasser D; Roux Lombard P; Vuilleumier N

来源：Journal of Internal Medicine, 2012, 272(4): 344-357.

DOI：10.1111/j.1365-2796.2012.02530.x

• anti-apolipoprotein A-1 auto-antibodies
• atherosclerosis
• inflammation
• molecular mimicry
• myocardial infarction
• toll-like receptors

. Pagano S, Satta N, Werling D, Offord V, de Moerloose P, Charbonney E, Hochstrasser D, Roux-Lombard P, Vuilleumier N (Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland; Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland; Royal Veterinary College, Hertfordshire, UK; St. Michaels Hospital, Toronto, Canada; Geneva University Hospital and Faculty of Medicine, Geneva, Switzerland). Anti-apolipoprotein A-1 IgG in patients with myocardial infarction promotes inflammation through TLR2/CD14 complex. J Intern Med 2012; 272: 344357. Objectives. Toll-like receptor (TLR)-mediated vascular inflammation, inducible by amongst other factors auto-antibodies, is increasingly recognized as a potential mediator of cardiovascular disease. We investigated whether anti-apolipoprotein (Apo)A-1 IgG was associated with a pro-inflammatory cytokine profile in myocardial infarction (MI) patients and whether anti-ApoA-1 IgG elicited a pro-inflammatory response by activating TLRs. Methods. As surrogate markers of atherosclerotic plaque vulnerability, interleukin (IL)-6, tumour necrosis factor (TNF)-a, matrix metalloproteinase (MMP)-9 and MMP-3 levels were assessed in 221 consecutive MI patients. Using human monocyte-derived macrophages (HMDMs) we investigated (i) the anti-ApoA-1 IgG interaction with TLRs using proximity ligation assay and (ii) anti-ApoA-1 IgG-dependent IL-6/TNF-a production. TLR involvement was further confirmed using HEK293-Blue TLR-2/-4 cells and by computational docking simulations. Results. In MI patients, anti-ApoA-1 IgG positivity was associated with higher levels of IL-6, TNF-a and MMP-9, but lower MMP-3 levels. In in vitro experiments, anti-ApoA-1 antibodies bound to HDMDs in a TLR2-dependent manner, resulting in nuclear translocation of NF?B and a significant increase in TNF-a and IL-6 production. Subsequent functional studies highlighted the importance of CD14 as co-receptor in the anti-ApoA-1 IgGTLR2-induced cytokine production. Additional bioinformatic studies identified structural homologies between TLR2 and ApoA-1, which may explain the observed cross-reactivity between antibodies against these two molecules. Conclusions. Anti-ApoA-1 IgG positivity in MI is associated with a high-risk cytokine profile. These auto-antibodies promote inflammation by stimulating the TLR2/CD14 receptor complex, probably because of molecular mimicry, which may contribute to atherosclerosis-related complications in patients.

• 出版日期2012-10