HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/1/L312    most recent 00250.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Skerrett, S. J. Articles by Hajjar, A. M. Search for Related Content PubMed PubMed Citation Articles by Skerrett, S. J. Articles by Hajjar, A. M.

Redundant Toll-like receptor signaling in the pulmonary host response to Pseudomonas aeruginosa

Departments of ¹Medicine, ²Immunology, and ³Comparative Medicine, University of Washington School of Medicine, Seattle, Washington

Submitted 30 June 2006 ; accepted in final form 22 August 2006

Activation of pulmonary defenses against Pseudomonas aeruginosa requires myeloid differentiation factor 88 (MyD88), an adaptor for Toll-like receptor (TLR) signaling. To determine which TLRs mediate recognition of P. aeruginosa, we measured cytokine responses of bone marrow cells from wild-type mice and mice lacking TLR2 (TLR2^–/–), TLR4 (TLR4^–/–), TLR2 and TLR4 (TLR2/4^–/–), or MyD88 (MyD88^–/–) to wild-type P. aeruginosa and to fliC P. aeruginosa, which lacks the TLR5 ligand flagellin. Mice also were challenged with aerosolized bacteria to determine cytokine responses, lung inflammation, and bacterial clearance. TNF induction required MyD88 and was absent in TLR2/4^–/– cells in response to fliC but not wild-type P. aeruginosa, whereas TLR2^–/– cells exhibited augmented responses. In vivo, TLR4^–/– mice responded to wild-type P. aeruginosa with reduced cytokine production and inflammation, but intact bacterial clearance, while TLR2^–/– mice had partially impaired cytokine responses and delayed bacterial killing despite normal inflammation. When challenged with fliC, MyD88^–/– mice failed to mount early cytokine and inflammatory responses or control bacterial replication, resulting in necrotizing lung injury and lethal disseminated infection. TLR4^–/– and TLR2/4^–/– mice responded to fliC infection with severely limited inflammatory and cytokine responses but intact bacterial clearance. TLR2^–/– mice had partially reduced cytokine responses but augmented inflammation and preserved bacterial killing. These data indicate that TLR4- and flagellin-induced signals mediate most of the acute inflammatory response to Pseudomonas and that TLR2 has a counterregulatory role. However, MyD88-dependent pathways, in addition to those downstream of TLR2, TLR4, and TLR5, are required for pulmonary defense against P. aeruginosa.

bacterial pneumonia; lung inflammation

This article has been cited by other articles:

				S. Cai, R. L. Zemans, S. K. Young, G. S. Worthen, and S. Jeyaseelan Myeloid Differentiation Protein-2-Dependent and -Independent Neutrophil Accumulation during Escherichia coli Pneumonia Am. J. Respir. Cell Mol. Biol., June 1, 2009; 40(6): 701 - 709. [Abstract] [Full Text] [PDF]

				J.-H. Park, Y.-G. Kim, and G. Nunez RICK Promotes Inflammation and Lethality after Gram-Negative Bacterial Infection in Mice Stimulated with Lipopolysaccharide Infect. Immun., April 1, 2009; 77(4): 1569 - 1578. [Abstract] [Full Text] [PDF]

				E. M. Bruscia, P.-X. Zhang, E. Ferreira, C. Caputo, J. W. Emerson, D. Tuck, D. S. Krause, and M. E. Egan Macrophages Directly Contribute to the Exaggerated Inflammatory Response in Cystic Fibrosis Transmembrane Conductance Regulator-/- Mice Am. J. Respir. Cell Mol. Biol., March 1, 2009; 40(3): 295 - 304. [Abstract] [Full Text] [PDF]

				H. von Bernuth, C. Picard, Z. Jin, R. Pankla, H. Xiao, C.-L. Ku, M. Chrabieh, I. B. Mustapha, P. Ghandil, Y. Camcioglu, et al. Pyogenic Bacterial Infections in Humans with MyD88 Deficiency Science, August 1, 2008; 321(5889): 691 - 696. [Abstract] [Full Text] [PDF]

				S. Hadina, J. P. Weiss, P. B. McCray Jr., K. Kulhankova, and P. S. Thorne MD-2-Dependent Pulmonary Immune Responses to Inhaled Lipooligosaccharides: Effect of Acylation State Am. J. Respir. Cell Mol. Biol., June 1, 2008; 38(6): 647 - 654. [Abstract] [Full Text] [PDF]

				C. Bretz, G. Gersuk, S. Knoblaugh, N. Chaudhary, J. Randolph-Habecker, R. C. Hackman, J. Staab, and K. A. Marr MyD88 Signaling Contributes to Early Pulmonary Responses to Aspergillus fumigatus Infect. Immun., March 1, 2008; 76(3): 952 - 958. [Abstract] [Full Text] [PDF]

				A. Didierlaurent, J. Goulding, S. Patel, R. Snelgrove, L. Low, M. Bebien, T. Lawrence, L. S. van Rijt, B. N. Lambrecht, J.-C. Sirard, et al. Sustained desensitization to bacterial Toll-like receptor ligands after resolutionof respiratory influenza infection J. Exp. Med., February 18, 2008; 205(2): 323 - 329. [Abstract] [Full Text] [PDF]

				R. S. Munford Sensing Gram-Negative Bacterial Lipopolysaccharides: a Human Disease Determinant? Infect. Immun., February 1, 2008; 76(2): 454 - 465. [Full Text] [PDF]