A novel pathway of cellular activation mediated by antiphospholipid antibody-induced extracellular vesicles.
J Thromb Haemost
; 13(10): 1928-40, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-26264622
ABSTRACT
BACKGROUND:
Elevated levels of endothelial cell (EC)-derived extracellular vesicles (EVs) circulate in patients with antiphospholipid antibodies (APLAs), and APLAs, particularly those against ß2 -glycoprotein I (ß2 GPI), stimulate EV release from ECs. However, the effects of EC-derived EVs have not been characterized.OBJECTIVE:
To determine the mechanism by which EVs released from ECs by anti-ß2 GPI antibodies activate unstimulated ECs. PATIENTS/METHODS:
We used interleukin (IL)-1 receptor inhibitors, small interfering RNA (siRNA) against Toll-like receptors (TLRs) and microRNA (miRNA) profiling to assess the mechanism(s) by which EVs released from ECs exposed to anti-ß2 GPI antibodies activated unstimulated ECs. RESULTS ANDCONCLUSIONS:
Anti-ß2 GPI antibodies caused formation of an EC inflammasome and the release of EVs that were enriched in mature IL-1ß, had a distinct miRNA profile, and caused endothelial activation. However, activation was not inhibited by an IL-1ß antibody, an IL-1 receptor antagonist, or IL-1 receptor siRNA. EC activation by EVs required IL-1 receptor-associated kinase 4 phosphorylation, and was inhibited by pretreatment of cells with TLR7 siRNA or RNase A, which degrades ssRNA. Profiling of miRNA in EVs released from ECs incubated with ß2 GPI and either control IgG or anti-ß2 GPI antibodies revealed numerous differences in the content of specific miRNAs, including a significant decrease in mIR126. These observations demonstrate that, although anti-ß2 GPI-derived endothelial EVs contain IL-1ß, they activate unstimulated ECs through a TLR7-dependent and ssRNA-dependent pathway. Alterations in miRNA content may contribute to the ability of EVs derived from ECs exposed to anti-ß2 GPI antibodies to activate unstimulated ECs in an autocrine or paracrine manner.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome Antifosfolipídica
/
Anticorpos Antifosfolipídeos
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Células Endoteliais
/
Beta 2-Glicoproteína I
/
Vesículas Extracelulares
Limite:
Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
J Thromb Haemost
Assunto da revista:
HEMATOLOGIA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos