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FMS-Like Tyrosine Kinase 3 Ligand Aggravates the Lung Inflammatory Response to Streptococcus pneumoniae Infection in Mice: Role of Dendritic Cells¹

Christine Winter^*, Katharina Taut^*, Florian Länger, Matthias Mack, David E. Briles, James C. Paton^¶, Regina Maus^*, Mrigank Srivastava^*, 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 Internal Medicine, University of Regensburg, Regensburg, Germany; Department of Microbiology, University of Alabama, Birmingham, AL 35294; and ^¶ School of Molecular and Biomedical Science, University of Adelaide, Adelaide, Australia

Pretreatment of mice with the hemopoietic growth factor, FMS-like tyrosine kinase 3 ligand (Flt3L), has been shown to increase monocyte-derived myeloid dendritic cells (DC) in lung parenchymal tissue, with possible implications for protective immunity to lung bacterial infections. However, whether Flt3L treatment improves lung innate immunity of mice to challenge with Streptococcus pneumoniae has not been investigated previously. Mice pretreated with Flt3L exhibited a peripheral monocytosis and a strongly expanded lung myeloid DC pool, but responded with a similar proinflammatory cytokine release (TNF-, IL-6, keratinocyte derived cytokine, MIP-2, CCL2) and neutrophilic alveolitis upon infection with S. pneumoniae as did control mice with a normal lung DC pool. Unexpectedly, however, Flt3L-pretreated mice, but not control mice, infected with S. pneumoniae developed vasculitis and increased lung permeability by days 2–3 postinfection, and florid pneumonia accompanied by sustained increased bacterial loads by days 3–4 postinfection. This was associated with an overall increased mortality of 35% by day 4 after pneumococcal challenge. Application of anti-CCR2 Ab MC21 to block inflammatory monocyte-dependent lung mononuclear phagocyte mobilization significantly reduced the lung leakage, but not vasculitis in Flt3L-pretreated mice infected with S. pneumoniae, without affecting the intra-alveolar cytokine liberation or the concomitantly developing neutrophilic alveolitis. Together, the data demonstrate that previous Flt3L-induced lung DC accumulation is not protective in lung innate immunity to challenge with S. pneumoniae, and support the concept that CCR2-dependent mononuclear phagocyte as opposed to neutrophil recruitment contributes to increased lung leakage in Flt3L-pretreated mice challenged with 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 This study has been supported by the German Research Foundation, Deutsche Forschungsgemeinschaft Grant SFB 587 (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: Flt3L, FMS-like tyrosine kinase 3 ligand; BAL, bronchoalveolar lavage; DC, dendritic cell; FSC, forward light scatter; KC, keratinocyte derived cytokine; SSC, side light scatter.

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