The role of TLR2 in the inflammatory activation of mouse fibroblasts by human antiphospholipid antibodies.
Antiphospholipid antibodies (APLAs) promote inflammatory and procoagulant responses in endothelial cells and monocytes. Previous studies have shown that MyD88, TRAF6, and NF-kappaB mediate cell activation by APLAs. These intermediates are also used by toll-like receptors (TLRs). We investigated the role of TLRs in the cellular response to APLAs. IgGs were isolated from the plasma of 5 patients with antiphospholipid syndrome along with immunopurified anti-beta2-glycoprotein 1 IgG from a sixth patient. Control IgG was obtained from a pool of healthy donor plasmas negative for APLAs. Wild-type mouse embryonic fibroblasts (EFs) and EFs deficient in TLR1, TLR2, TLR4, or TLR6 were incubated with APLAs, anti-beta2-glycoprotein 1 IgG, or control IgG. On incubation with the patient IgG, but not control IgG, a significant increase in mRNA levels of the inflammatory marker proteins MCP-1, ICAM-1, and IL-6 as well as IL-6 secretion was observed in wild-type EFs, whereas TLR2-deficient EFs did not respond. Responses in TLR1- and TLR6-deficient EFs were decreased and those in TLR4-deficient EFs comparable to those in wild-type EFs. Overexpression of human TLR2 in the TLR2-deficient EFs restituted the response to patient IgG. Our results imply that TLR2 plays a role in mouse fibroblast activation by APLAs.
Satta
Nathalie
N
Division of Angiology and Hemostasis, University Hospital, Faculty of Medicine, Geneva, Switzerland.
Dunoyer-Geindre
Sylvie
S
Reber
Guido
G
Fish
Richard J
RJ
Boehlen
Francoise
F
Kruithof
Egbert K O
EK
de Moerloose
Philippe
P
D000818:Animals; D017152:Antibodies, Antiphospholipid; D015415:Biomarkers / Q000097:blood; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000502:physiology*; D053482:beta 2-Glycoprotein I / Q000276:immunology
D017152:Antibodies, Antiphospholipid; D015415:Biomarkers; D007074:Immunoglobulin G; D012333:RNA, Messenger; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D053482:beta 2-Glycoprotein I