TY - JOUR

T1 - Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies

AU - Tsiantoulas, Dimitrios

AU - Perkmann, Thomas

AU - Afonyushkin, Taras

AU - Mangold, Andreas

AU - Prohaska, Thomas A.

AU - Papac-Milicevic, Nikolina

AU - Millischer, Vincent

AU - Bartel, Caroline

AU - Hörkkö, Sohvi

AU - Boulanger, Chantal M.

AU - Tsimikas, Sotirios

AU - Fischer, Michael B.

AU - Witztum, Joseph L.

AU - Lang, Irene M.

AU - Binder, Christoph J.

PY - 2015/2

Y1 - 2015/2

N2 - Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monocytes to produce interleukin 8, which can be inhibited by a monoclonal IgM with specificity for MDA epitopes. Finally, we show that MDA+ MPs are elevated at the culprit lesion site of patients with STE-MI. Our results identify a subset of OSE+ MPs that are bound by OxLDL-specific IgM. These findings demonstrate a novel mechanism by which anti-OxLDL IgM antibodies could mediate protective functions in CVD.

AB - Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monocytes to produce interleukin 8, which can be inhibited by a monoclonal IgM with specificity for MDA epitopes. Finally, we show that MDA+ MPs are elevated at the culprit lesion site of patients with STE-MI. Our results identify a subset of OSE+ MPs that are bound by OxLDL-specific IgM. These findings demonstrate a novel mechanism by which anti-OxLDL IgM antibodies could mediate protective functions in CVD.

KW - immunoglobulin M antibodies

KW - malondialdehyde

KW - acute coronary syndrome

U2 - 10.1194/jlr.P054569

DO - 10.1194/jlr.P054569

M3 - Article

VL - 56.2015

SP - 440

EP - 448

JO - Journal of lipid research

JF - Journal of lipid research

SN - 0022-2275

IS - 2

ER -