Down-regulation of endothelial TLR4 signalling after apo A-I gene transfer contributes to improved survival in an experimental model of lipopolysaccharide-induced inflammation.
The protective effects of high-density lipoprotein (HDL) under lipopolysaccharide (LPS) conditions have been well documented. Here, we investigated whether an effect of HDL on Toll-like receptor 4 (TLR4) expression and signalling may contribute to its endothelial-protective effects and to improved survival in a mouse model of LPS-induced inflammation and lethality. HDL cholesterol increased 1.7-fold (p<0.005) and lung endothelial TLR4 expression decreased 8.4-fold (p<0.005) 2 weeks after apolipoprotein (apo) A-I gene transfer. Following LPS administration in apo A-I gene transfer mice, lung TLR4 and lung MyD88 mRNA expression, reflecting TLR4 signalling, were 3.0-fold (p<0.05) and 2.1-fold (p<0.05) lower, respectively, than in LPS control mice. Concomitantly, LPS-induced lung neutrophil infiltration, lung oedema and mortality were significantly attenuated following apo A-I transfer. In vitro, supplementation of HDL or apo A-I to human microvascular endothelial cells-1 24 h before LPS administration reduced TLR4 expression, as assessed by fluorescent-activated cell sorting, and decreased the LPS-induced MyD88 mRNA expression and NF-κB activity, independently of LPS binding. In conclusion, HDL reduces TLR4 expression and signalling in endothelial cells, which may contribute significantly to the protective effects of HDL in LPS-induced inflammation and lethality.
Department of Cardiology & Pneumology, Charité-University-Medicine Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200, Berlin, Germany.
Sophie
S
Van Linthout
Frank
F
Spillmann
Gallia
G
Graiani
Kapka
K
Miteva
Jun
J
Peng
Eline
E
Van Craeyveld
Marco
M
Meloni
Markus
M
Tölle
Felicitas
F
Escher
Aysun
A
Subasigüller
Wolfram
W
Doehner
Federico
F
Quaini
Bart
B
De Geest
Heinz-Peter
HP
Schultheiss
Carsten
C
Tschöpe
D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D016019:Survival Analysis; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D016632:Apolipoprotein A-I; D008070:Lipopolysaccharides; D008075:Lipoproteins, HDL; D051197:Toll-Like Receptor 4