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(TRIF)-Mediated Signaling Contributes to Innate Immune Responses in the Lung during Escherichia coli Pneumonia1
* Division of Respiratory Infections, Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206;
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; and
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
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-
(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-
B activation; and TNF-
, 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- and IL-6 production was attenuated in BMMs of TRIF–/– mice. E. coli LPS-induced late MAPK activation, and TNF- 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- 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a grant from the University of Colorado Health Sciences Center (to S.J.), a biomedical research grant from the American Lung Association (RG-22442-N; to S.J.), a grant from the American Heart Association (0275035N; to M.B.F.), and a grant from the National Institutes of Health (HL-068876; to G.S.W.).
2 Address correspondence and reprint requests to Dr. Samithamby Jeyaseelan, Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street Neustadt D-403, Denver, CO 80206. E-mail address: JeyaseelanS{at}njc.org
3 Abbreviations used in this paper: TIR, Toll/IL-1R; AM, alveolar macrophage; BALF, bronchoalveolar lavage fluid; BMM, bone marrow-derived macrophage; i.t., intratracheal; KC, keratinocyte cell-derived chemokine; LIX, LPS-induced C-X-C chemokine; TIRAP, TIR domain-containing adaptor protein; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain-containing adaptor inducing IFN-; TSA, tryptic soy agar.
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