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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 297/4/L608    most recent 90433.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Cabanski, M. Articles by Lohmeyer, J. PubMed PubMed Citation Articles by Cabanski, M. Articles by Lohmeyer, J.

Genome-wide transcriptional profiling of mononuclear phagocytes recruited to mouse lungs in response to alveolar challenge with the TLR2 agonist Pam₃CSK₄

Maciej Cabanski,^1,3,* Jochen Wilhelm,^2,* Zbigniew Zasona,¹ Mirko Steinmüller,¹ Ludger Fink,² Werner Seeger,¹ and Jürgen Lohmeyer¹

¹Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Infectious Diseases, and ; ²Department of Pathology, Justus Liebig University, Giessen; and ; ³Department of Paediatrics, Division of Pulmonology and Neonatology, Hannover Medical School, Hannover, Germany

Submitted 7 August 2008 ; accepted in final form 12 July 2009

Compared with the Toll-like receptor 4 (TLR4) ligand LPS restricted to Gram-negative bacteria, few studies have addressed induction of lung inflammation and concomitant leukocyte recruitment in response to TLR2 ligands. This study is the first report showing that selective TLR2 stimulation by its ligand Pam₃-Cys-Ser-Lys-Lys-Lys-Lys-OH (Pam₃CSK₄) within the alveolar compartment promoted lung inflammation in mice and induced the migration of circulatory immune cells including mononuclear phagocytes into the inflamed alveolar space. By using the transgenic CX₃CR1^+/GFP mouse strain for high-purity sorting of circulating and alveolar recruited mononuclear phagocytes together with SMART preamplification and whole genome oligonucleotide microarray techniques, we found that alveolar trafficking of mononuclear phagocytes was associated with profound changes of their gene expression profiles (900 differentially regulated genes postrecruitment). In particular, alveolar recruited mononuclear phagocytes showed upregulated transcripts of genes encoding cytokines/chemokines and pattern recognition receptor (PRR)-associated molecules. Notably, we observed a dynamic change of the genetic program of recruited mononuclear phagocytes obtained from bronchoalveolar lavage fluid at different time points (24 vs. 48 h) post-Pam₃CSK₄ challenge. In early alveolar recruited mononuclear phagocytes, mRNA levels of both proinflammatory (e.g., TNF-, CCL2, and IL-6) and central anti-inflammatory/ proresolution [e.g., IL-1-receptor antagonist (IL-1RN), CD200 receptor (CD200R), IL-1 receptor-associated kinase (IRAK-M), IL-10, and Bcl-2-associated X protein (Bax)] mediators were found to be highly upregulated simultaneously. In corresponding cells recruited until later time points, transcript levels of anti-inflammatory/proresolution molecules persisted at the same level, whereas mRNA levels of proinflammatory mediators were found to decline. Collectively, our in vivo study identifies genetic programs by which alveolar recruited mononuclear phagocytes may contribute to the development and termination of pneumonia caused by Gram-positive bacteria.

Toll-like receptor