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Important Role for CC Chemokine Ligand 2-Dependent Lung Mononuclear Phagocyte Recruitment to Inhibit Sepsis in Mice Infected with Streptococcus pneumoniae ¹

Christine Winter^*, Wiebke Herbold^*, Regina Maus^*, Florian Länger, David E. Briles, James C. Paton, Tobias Welte^* 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 Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294; and School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia

The monocyte chemoattractant CCL2 is of major importance in inflammatory monocyte recruitment to the lungs in response to bacterial infection. Streptococcus pneumoniae is the most prevalent pathogen in community-acquired pneumonia causing significant morbidity and mortality worldwide. In the current study, we examined the role of CCL2 in lung-protective immunity against two strains of S. pneumoniae exhibiting different virulence profiles. Both wild-type mice and CCL2 knockout (KO) mice became septic within 24 h of infection with serotype 3 S. pneumoniae and died of infection by day 4 after challenge. In contrast, wild-type mice challenged with serotype 19 S. pneumoniae did not become septic or succumb to pneumococcal pneumonia, whereas CCL2 KO mice showed an early bacterial outgrowth in their lungs and sepsis starting by day 2 after infection, finally resulting in 50% decreased survival compared with wild-type mice. This phenotype was not due to impaired lung neutrophil recruitment in the KO mice, but was characterized by a significantly reduced recruitment of lung exudate macrophages and conventional lung dendritic cells, suggesting that these two phagocyte subsets critically regulate protection against septic disease progression in mice. In conclusion, we show here a differential role for CCL2-dependent lung exudate macrophage and conventional dendritic cell recruitment that critically contributes to lung protective immunity against S. pneumoniae.

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 The current study has been supported by the German Research Council (Deutsche Forschungsgemeinschaft), Grant SFB 587 (to U.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: WT, wild type; KO, knockout; THB, Todd-Hewitt broth; BAL, bronchoalveolar lavage; FSC-A, forward scatter area; MHCII, MHC class II; DC, dendritic cell.