TLR4 gene dosage contributes to endotoxin-induced acute respiratory inflammation.
Toll-like receptor (TLR)4 is critical for endotoxin recognition and cellular responses. Using Tlr4 transgenic mice, we investigated the influence of Tlr4 gene dosage on acute respiratory response to endotoxin. Transgenic mice expressing three, six, or 30 copies of Tlr4, control, and Tlr4-deficient mice received intranasal administration of lipopolysaccharide (LPS; 10 ug), and the airway response was analyzed by plethysmography, lung histology, cell recruitment, cytokine and chemokine secretion and protein leakage into the bronchoalveolar space. We demonstrate that overexpression of Tlr4 augmented a LPS-induced bronchoconstrictive effect, as well as tumor necrosis factor and CXC chemokine ligand 1 (keratinocyte-derived chemokine) production. Neutrophil recruitment, microvascular and alveolar epithelial injury with protein leak in the airways, and damage of the lung microarchitecture were Tlr4 gene dose-dependently increased. Therefore, the TLR4 expression level determines the extent of acute pulmonary response to inhaled endotoxin, and TLR4 may thus be a valuable target for immunointervention in acute lung inflammation as a result of endotoxins.
Togbe
Dieudonnée
D
CNRS, UMR 6218, Molecular Immunology and Embryology Transgenose Institute, UMR6218, 3b rue de la Ferollerie, 45071 Orléans Cédex 2, France.
Schnyder-Candrian
Silvia
S
Schnyder
Bruno
B
Couillin
Isabelle
I
Maillet
Isabelle
I
Bihl
Franck
F
Malo
Danielle
D
Ryffel
Bernhard
B
Quesniaux
Valerie F J
VF
D000208:Acute Disease; D000281:Administration, Intranasal; D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D018628:Gene Dosage / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D011014:Pneumonia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology*
D016207:Cytokines; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4