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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0803862v1 183/3/2027    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Lagler, H. Articles by Knapp, S. PubMed PubMed Citation Articles by Lagler, H. Articles by Knapp, S.

TREM-1 Activation Alters the Dynamics of Pulmonary IRAK-M Expression In Vivo and Improves Host Defense during Pneumococcal Pneumonia¹

Heimo Lagler^2,, Omar Sharif^2,*, Isabella Haslinger, Ulrich Matt^*,, Karin Stich, Tanja Furtner^*,, Bianca Doninger^*,, Katharina Schmid, Rainer Gattringer, Alex F. de Vos and Sylvia Knapp^3,*,

^* Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria; Department of Medicine I, Division of Infectious Diseases and Tropical Medicine and Clinical Department of Pathology, Medical University Vienna, Vienna, Austria; and Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Triggering receptor expressed on myeloid cells-1 (TREM-1) is an amplifier of TLR-mediated inflammation during bacterial infections. Thus far, TREM-1 is primarily associated with unwanted signs of overwhelming inflammation, rendering it an attractive target for conditions such as sepsis. Respiratory tract infections are the leading cause of sepsis, but the biological role of TREM-1 therein is poorly understood. To determine the function of TREM-1 in pneumococcal pneumonia, we first established TREM-1 up-regulation in infected lungs and human plasma together with augmented alveolar macrophage responsiveness toward Streptococcus pneumoniae. Mice treated with an agonistic TREM-1 Ab and infected with S. pneumoniae exhibited an enhanced early induction of the inflammatory response that was indirectly associated with lower levels of negative regulators of TLR signaling in lung tissue in vivo. Later in infection, TREM-1 engagement altered S. pneumoniae-induced IRAK-M (IL-1R-associated kinase-M) kinetics so as to promote the resolution of pneumonia and remarkably led to an accelerated elimination of bacteria and consequently improved survival. These data show that TREM-1 exerts a protective role in the innate immune response to a common bacterial infection and suggest that caution should be exerted in modulating TREM-1 activity during certain clinically relevant bacterial infections.

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 in part by grants from the Jubiläumsfond der Stadt Wien (to S.K.) and the Austrian Society of Antimicrobial Chemotherapy (to S.K.).

² H.L. and O.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Sylvia Knapp, Center for Molecular Medicine of the Austrian Academy of Sciences and Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University, Vienna, Austria, Währinger Gürtel 18-20, 1090 Vienna, Austria. E-mail address: sylvia.knapp{at}meduniwien.ac.at

⁴ Abbreviations used in this paper: TREM-1, triggering receptor expressed on myeloid cells-1; AM, alveolar macrophage; BAL, bronchoalveolar lavage; BALF, BAL fluid; IRAK-M, IL-1R-associated kinase-M; KC, keratinocyte-derived chemokine; MPO, myeloperoxidase; PRR, pattern recognition receptor; shRNAi, short hairpin RNA interference; sTREM-1, soluble TREM-1; Tollip, Toll-interacting protein.