title: Redundant Toll-like receptor signaling in the pulmonary host response to Pseudomonas aeruginosa.
abstract: 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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Harborview Medical Center, 325 Ninth Avenue, Box 359640, Seattle, WA 98104, USA. shawn@u.washington.edu
authors.forename: Shawn J
authors.initials: SJ
authors.lastname: Skerrett
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Wilson
authors.forename: H Denny
authors.initials: HD
authors.lastname: Liggitt
authors.forename: Adeline M
authors.initials: AM
authors.lastname: Hajjar
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000382:microbiology; D016207:Cytokines / Q000096:biosynthesis; D005408:Flagellin / Q000235:genetics; D066298:In Vitro Techniques; D008168:Lung / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D008171:Lung Diseases / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics; D011552:Pseudomonas Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000472:pathogenicity*; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D016207:Cytokines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D005408:Flagellin