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Leukotriene B₄ Induces Release of Antimicrobial Peptides in Lungs of Virally Infected Mice¹

Laboratory of Viral Immunology, Rheumatology and Immunology Research Center, Centre Hospitalier de l’Université Laval Research Center, and Université Laval, Quebec, Canada

Leukotriene B₄ (LTB₄) is a lipid mediator of inflammation that was recently shown to exert antiviral activities. In this study, we demonstrate that the release of antimicrobial proteins by neutrophils contribute to an early host defense against influenza virus infection in vitro as well as in vivo. Daily i.v. treatments with LTB₄ lead to a significant decrease in lung viral loads at day 5 postinfection in mice infected with influenza A virus compared with the placebo-treated group. This reduction in viral load was not present in mice deficient in the high-affinity LTB₄ receptor. Viral clearance in lungs was associated with up-regulated presence of antimicrobial peptides such as β-defensin-3, members of the mouse eosinophil-related RNase family, and the mouse cathelicidin-related antimicrobial peptide. Our results also indicate that neutrophils are important in the antiviral effect of LTB₄. Viral loads in neutrophil-depleted mice were not diminished by LTB₄ administration, and a substantial reduction in the presence of murine cathelicidin-related antimicrobial peptide and the murine eosinophil-related RNase family in lung tissue was observed. Moreover, in vitro treatment of human neutrophil cultures with LTB₄ led rapidly to the secretion of the human cathelicidin LL-37 and eosinophil-derived neurotoxin, known as antiviral peptides. Pretreatment of cell cultures with specific LTB₄ receptor antagonists clearly demonstrate the implication of the high-affinity LTB₄ receptor in the LTB₄-mediated activity. Together, these results demonstrate the importance of neutrophils and the secretion of antimicrobial peptides during the early immune response mediated by LTB₄ against a viral 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 Canadian Institutes of Health Research (to J.G.).

² Address correspondence and reprint requests to Dr. Jean Gosselin, Laboratory of Viral Immunology, Rheumatology and Immunology Research Center, Centre Hospitalier de l’Université Laval Research Center, Room T 1-49, 2705 Boulevard Laurier, Quebec, G1V 4G2, Canada. E-mail address: jean.gosselin{at}crchul.ulaval.ca

³ Abbreviations used in this paper: LTB₄, leukotriene B₄; CRAMP, cathelicidin-related antimicrobial peptide; EDN, eosinophil-derived neurotoxin; mEARs, murine eosinophil-associated RNase family; MDCK, Madin-Darby canine kidney.