Nonredundant roles of TIRAP and MyD88 in airway response to endotoxin, independent of TRIF, IL-1 and IL-18 pathways.
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.
Togbe
Dieudonnée
D
Molecular Immunology and Embryology, CNRS UMR6218, Transgenose Institute, Orleans, France.
Aurore
Gorse
G
Noulin
Nicolas
N
Quesniaux
Valérie F J
VF
Schnyder-Candrian
Silvia
S
Schnyder
Bruno
B
Vasseur
Virginie
V
Akira
Shizuo
S
Hoebe
Kasper
K
Beutler
Bruce
B
Ryffel
Bernhard
B
Couillin
Isabelle
I
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D016084:Bronchoconstriction / Q000187:drug effects*; D002478:Cells, Cultured; D004731:Endotoxins / Q000633:toxicity*; D007375:Interleukin-1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000502:physiology*
D033942:Adaptor Proteins, Vesicular Transport; D004731:Endotoxins; D007375:Interleukin-1; D020382:Interleukin-18; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D009195:Peroxidase; D017472:Receptors, Interleukin-1; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C499045:TIRAP protein, mouse; C044101:endotoxin, Escherichia coli