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Lung-Specific Overexpression of CC Chemokine Ligand (CCL) 2 Enhances the Host Defense to Streptococcus pneumoniae Infection in Mice: Role of the CCL2-CCR2 Axis¹

Christine Winter^*, Katharina Taut^*, Mrigank Srivastava^*, Florian Länger, Matthias Mack, David E. Briles, James C. Paton^¶, Regina Maus^*, Tobias Welte^*, Michael D. Gunn^|| and Ulrich A. Maus^2,*

^* Department of Pulmonary Medicine, Laboratory for Experimental Lung Research, and Department of Pathology, Hannover School of Medicine, Hannover, Germany; Department of Internal Medicine, University of Regensburg, Regensburg, Germany; Department of Microbiology, University of Alabama, Birmingham, AL 35294; ^¶ School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia; and ^|| Department of Medicine, Duke University Medical Center, Durham, NC 27710

Mononuclear phagocytes are critical components of the innate host defense of the lung to inhaled bacterial pathogens. The monocyte chemotactic protein CCL2 plays a pivotal role in inflammatory mononuclear phagocyte recruitment. In this study, we tested the hypothesis that increased CCL2-dependent mononuclear phagocyte recruitment would improve lung innate host defense to infection with Streptococcus pneumoniae. CCL2 transgenic mice that overexpress human CCL2 protein in type II alveolar epithelial cells and secrete it into the alveolar air space showed a similar proinflammatory mediator response and neutrophilic alveolitis to challenge with S. pneumoniae as wild-type mice. However, CCL2 overexpressing mice showed an improved pneumococcal clearance and survival compared with wild-type mice that was associated with substantially increased lung mononuclear phagocyte subset accumulations upon pneumococcal challenge. Surprisingly, CCL2 overexpressing mice developed bronchiolitis obliterans upon pneumococcal challenge. Application of anti-CCR2 Ab MC21 to block the CCL2-CCR2 axis in CCL2 overexpressing mice, though completely abrogating bronchiolitis obliterans, led to progressive pneumococcal pneumonia. Collectively, these findings demonstrate the importance of the CCL2-CCR2 axis in the regulation of both the resolution/repair and remodelling processes after bacterial challenge and suggest that overwhelming innate immune responses may trigger bronchiolitis obliterans formation in bacterial lung 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 study has been supported by Deutsche Forschungsgemeinschaft Grant SFB 587 from the German Research Foundation (to U.A.M. and T.W.).

² Address correspondence and reprint requests to Dr. Ulrich A. Maus, Department of Pulmonary Medicine, Laboratory for Experimental Lung Research, Hannover School of Medicine, Hannover 30625, Germany. E-mail address: Maus.Ulrich{at}mh-hannover.de

³ Abbreviations used in this paper: BAL, bronchoalveolar lavage; ARDS, acute respiratory distress syndrome; DC, dendritic cell; MHC-II, MHC class II; FSC, forward light scatter; SSC, side light scatter.

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