title: Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-mediated signaling contributes to innate immune responses in the lung during Escherichia coli pneumonia.
abstract: Bacterial pneumonia remains a serious disease and is associated with neutrophil recruitment. Innate immunity is pivotal for the elimination of bacteria, and TLRs are essential in this process. Toll/IL-1R domain-containing adaptor inducing IFN-beta (TRIF) is an adaptor for TLR3 and TLR4, and is associated with the MyD88-independent cascade. However, the importance of TRIF in immune responses against pulmonary bacterial pathogens is not well understood. We investigated the involvement of TRIF in a murine model of Escherichia coli pneumonia. TRIF(-/-) mice infected with E. coli display attenuated neutrophil migration; NF-kappaB activation; and TNF-alpha, IL-6, and LPS-induced C-X-C chemokine production in the lungs. In addition, E. coli-induced phosphorylation of JNK, ERK, and p38 MAPK was detected in bone marrow-derived macrophages (BMMs) of TRIF(+/+) mice, but attenuated in BMMs of TRIF(-/-) mice. Furthermore, E. coli-induced TNF-alpha and IL-6 production was attenuated in BMMs of TRIF(-/-) mice. E. coli LPS-induced late MAPK activation, and TNF-alpha and IL-6 production were abolished in BMMs of TRIF(-/-) mice. Moreover, TRIF is not required for LPS-induced neutrophil influx, and keratinocyte cell-derived chemokine, MIP-2, and LPS-induced C-X-C chemokine production in the lungs. Using TLR3(-/-) mice, we ruled out the role of TLR3-mediated TRIF-dependent neutrophil influx during E. coli pneumonia. A TLR4-blocking Ab inhibited E. coli-induced TNF-alpha and IL-6 in BMMs of both TRIF(-/-) and TRIF(+/+) mice, suggesting that TRIF-mediated signaling involves TLR4. We also found that TRIF is critical to control E. coli burden in the lungs and E. coli dissemination. Thus, rapid activation of TRIF-dependent TLR4-mediated signaling cascade serves to augment pulmonary host defense against a Gram-negative pathogen.
authors.affiliation: Division of Respiratory Infections, Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street Neustadt D-403, Denver, CO 80206, USA. JeyaseelanS@njc.org
authors.forename: Samithamby
authors.initials: S
authors.lastname: Jeyaseelan
authors.forename: Scott K
authors.initials: SK
authors.lastname: Young
authors.forename: Michael B
authors.initials: MB
authors.lastname: Fessler
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Malcolm
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000276:immunology*; D000818:Animals; D016207:Cytokines / Q000276:immunology; D004926:Escherichia coli / Q000276:immunology*; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D015603:Keratinocytes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000382:microbiology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000172:deficiency / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D020929:Mitogen-Activated Protein Kinase Kinases; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse