TLR4 gene dosage contributes to endotoxin-induced acute respiratory inflammation

Journal of Leukocyte Biology

Isabelle Couillin²  Isabelle Maillet²  Bruno Schnyder³  Silvia Schnyder-Candrian²  Franck Bihl²  Valerie F. J. Quesniaux²  Dieudonnée Togbe²  Bernhard Ryffel²  Danielle Malo¹ 

[1] Biomedical Research Foundation, SBF, Matzingen, Switzerland; and Biomedical Research Foundation, SBF, Matzingen, Switzerland; and Biomedical Research Foundation, SBF, Matzingen, Switzerland; and;CNRS (Centre National de la Recherche Scientifique), Molecular Immunology and Embryology UMR6218, Orléans, France; and CNRS (Centre National de la Recherche Scientifique), Molecular Immunology and Embryology UMR6218, Orléans, France; and CNRS (Centre National de la Recherche Scientifique), Molecular Immunology and Embryology UMR6218, Orléans, France; and;CNRS (Centre National de la Recherche Scientifique), Molecular Immunology and Embryology UMR6218, Orléans, France; and Department of Medicine and Human Genetics, McGill University, Montréal, Québec, Canada CNRS (Centre National de la Recherche Scientifique), Molecular Immunology and Embryology UMR6218, Orléans, France; and CNRS (Centre National de la Recherche Scientifique), Molecular Immunology and Embryology UMR6218, Orléans, France; and Department of Medicine and Human Genetics, McGill University, Montréal, Québec, Canada Department of Medicine and Human Genetics, McGill University, Montréal, Québec, Canada CNRS (Centre National de la Recherche Scientifique), Molecular Immunology and Embryology UMR6218, Orléans, France; and Department of Medicine and Human Genetics, McGill University, Montréal, Québec, Canada

关键词: lung;    lipopolysaccharide;    CXCL1;    KC;    Toll-like receptor transgenic mice;    vascular leak;   

DOI  :  10.1189/jlb.0206099

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown