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A Role of Toll-IL-1 Receptor Domain-Containing Adaptor-Inducing IFN- in the Host Response to Pseudomonas aeruginosa Lung Infection in Mice¹

Melanie R. Power^*, Bo Li^*, Masahiro Yamamoto, Shizuo Akira and Tong-Jun Lin^2,

^* Department of Microbiology and Immunology, and Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Toll-IL-1R domain-containing adaptor-inducing IFN- (TRIF) is an adaptor molecule that mediates a distinct TLR signaling pathway. Roles of TRIF in the host defense have been primarily associated with virus infections owing to the induction of IFN-. In this study, we investigated a role of TRIF in Pseudomonas aeruginosa infection. In vitro, TRIF-deficient mouse alveolar and peritoneal macrophages showed a complete inhibition of RANTES (CCL5) production, severely impaired TNF and KC (CXCL1) production, and reduced NF-B activation in response to P. aeruginosa stimulation. In vivo, TRIF-deficient mice showed a complete inhibition of RANTES production, a severely impaired TNF and KC production, and an efficient MIP-2 and IL-1 production in the lung following P. aeruginosa infection. This outcome was associated with a delayed recruitment of neutrophils into the airways. These results suggest that TRIF mediates a distinct cytokine/chemokine profile in response to P. aeruginosa infection. P. aeruginosa-induced RANTES production is completely dependent on TRIF pathway in mice. Importantly, TRIF deficiency leads to impaired clearance of P. aeruginosa from the lung during the initial 24–48 h of infection. Thus, TRIF represents a novel mechanism involved in the development of host response to P. aeruginosa infection.

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 grants from the Canadian Institutes of Health Research, Canadian Cystic Fibrosis Foundation, and Izaak Walton Killam Health Center. T.J.L. is supported by a New Investigator Award from the Canadian Institutes of Health Research and an Investigatorship from Izaak Walton Killam Health Center.

² Address correspondence and reprint requests to Dr. Tong-Jun Lin, Izaak Walton Killam Health Center, 5850 University Avenue, Halifax, Nova Scotia B3K 6R8, Canada. E-mail address: tong-jun.lin{at}dal.ca

³ Abbreviations used in this paper: TRIF, Toll-IL-1R domain-containing adaptor-inducing IFN-; IRF, IFN regulatory factor; BALF, bronchoalveolar lavage fluid; MOI, multiplicity of infection; MPO, myeloperoxidase.

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