TY - JOUR
T1 - Nonredundant roles of TIRAP and MyD88 in airway response to endotoxin, independent of TRIF, IL-1 and IL-18 pathways
AU - Togbe, Dieudonnée
AU - Aurore, Gorse
AU - Noulin, Nicolas
AU - Quesniaux, Valérie F J
AU - Schnyder-Candrian, Silvia
AU - Schnyder, Bruno
AU - Vasseur, Virginie
AU - Akira, Shizuo
AU - Hoebe, Kasper
AU - Beutler, Bruce
AU - Ryffel, Bernhard
AU - Couillin, Isabelle
N1 - Funding Information:
Grant support by the French ‘Ministère de l’Education Nationale, de la Recherche et de la Technologie’ (to Nicolas Noulin), Fondation de la Recherche and CNRS. The work was also supported by grants from Le Studium (Orleans), and Fondation de la Recherche Médicale. We acknowledge the skilled technical assistance of Marielle Maret and Lizette Fick.
Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/10/21
Y1 - 2006/10/21
N2 - Inhaled endotoxins induce an acute inflammatory response in the airways mediated through Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). However, the relative roles of the TLR4 adaptor proteins TIRAP and TRIF and of the MyD88-dependent IL-1 and IL-18 receptor pathways in this response are unclear. Here, we demonstrate that endotoxin-induced acute bronchoconstriction, vascular damage resulting in protein leak, Th1 cytokine and chemokine secretion and neutrophil recruitment in the airways are abrogated in mice deficient for either TIRAP or MyD88, but not in TRIF deficient mice. The contribution of other TLR-independent, MyD88-dependent signaling pathways was investigated in IL-1R1, IL-18R and caspase-1 (ICE)-deficient mice, which displayed normal airway responses to endotoxin. In conclusion, the TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin critically depend on the expression of both adaptor proteins, TIRAP and MyD88, suggesting cooperative roles, while TRIF, IL-1R1, IL-18R signaling pathways are dispensable.
AB - Inhaled endotoxins induce an acute inflammatory response in the airways mediated through Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). However, the relative roles of the TLR4 adaptor proteins TIRAP and TRIF and of the MyD88-dependent IL-1 and IL-18 receptor pathways in this response are unclear. Here, we demonstrate that endotoxin-induced acute bronchoconstriction, vascular damage resulting in protein leak, Th1 cytokine and chemokine secretion and neutrophil recruitment in the airways are abrogated in mice deficient for either TIRAP or MyD88, but not in TRIF deficient mice. The contribution of other TLR-independent, MyD88-dependent signaling pathways was investigated in IL-1R1, IL-18R and caspase-1 (ICE)-deficient mice, which displayed normal airway responses to endotoxin. In conclusion, the TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin critically depend on the expression of both adaptor proteins, TIRAP and MyD88, suggesting cooperative roles, while TRIF, IL-1R1, IL-18R signaling pathways are dispensable.
KW - Airways response
KW - Caspase-1
KW - Endotoxin
KW - Innate immunity
KW - TLR signaling
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U2 - 10.1038/labinvest.3700473
DO - 10.1038/labinvest.3700473
M3 - Article
C2 - 16983331
AN - SCOPUS:33750291430
SN - 0023-6837
VL - 86
SP - 1126
EP - 1135
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 11
ER -