1. ¹Molecular Immunology and Embryology, CNRS UMR6218, Transgenose Institute, Orleans, France
2. ²R&D Department, Key-Obs, Orleans, France
3. ³Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan
4. ⁴Department of Immunology, Scripps Research Institute, La Jolla, CA, USA

Correspondence: Dr I Couillin, PhD, Molecular Immunology and Embryology, Transgenic Institute, CNRS UMR6218, 3 B Rue de la Ferollerie, Orleans Cedex 2 45071, France. E-mails: couillin@cnrs-orleans.fr, bryffel@cnrs-orleans.fr

^*Senior authorship shared IC and BR.

Received 25 May 2006; Revised 13 July 2006; Accepted 16 July 2006; Published online 18 September 2006.

Abstract

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.