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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Thromb+Haemost
2015 ; 13
(10
): 1928-40
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A novel pathway of cellular activation mediated by antiphospholipid
antibody-induced extracellular vesicles
#MMPMID26264622
Wu M
; Barnard J
; Kundu S
; McCrae KR
J Thromb Haemost
2015[Oct]; 13
(10
): 1928-40
PMID26264622
show ga
BACKGROUND: Elevated levels of endothelial cell (EC)-derived extracellular
vesicles (EVs) circulate in patients with antiphospholipid antibodies (APLAs),
and APLAs, particularly those against ?2 -glycoprotein I (?2 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-?2 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-?2 GPI antibodies
activated unstimulated ECs. RESULTS AND CONCLUSIONS: Anti-?2 GPI antibodies
caused formation of an EC inflammasome and the release of EVs that were enriched
in mature IL-1?, had a distinct miRNA profile, and caused endothelial activation.
However, activation was not inhibited by an IL-1? 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 ?2 GPI and either control IgG or anti-?2 GPI
antibodies revealed numerous differences in the content of specific miRNAs,
including a significant decrease in mIR126. These observations demonstrate that,
although anti-?2 GPI-derived endothelial EVs contain IL-1?, 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-?2 GPI antibodies to activate unstimulated ECs in an
autocrine or paracrine manner.
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