title: Macrolides Promote CCL2-Mediated Macrophage Recruitment and Clearance of Nasopharyngeal Pneumococcal Colonization in Mice.
abstract: BACKGROUND
  Streptococcus pneumoniae (pneumococcus) colonizes mucosal surfaces of the upper respiratory tract (URT), resulting in invasive disease. Macrolides are known for their immunomodulatory effects. We investigated the potency of macrolides to reduce pneumococcal colonization by activating host innate immunity.
  
  
  METHODS
  The kinetics of colonization, cellular response, and inflammatory cytokine levels in the URT were assessed after nasal inoculation of pneumococci. EM900 (a novel 12-membered nonantibiotic macrolide with an immunomodulatory effect) was orally administered throughout the experiment. Survival was evaluated for 10 days. Macrolide-mediated CCL2 production from peritoneal macrophages was determined by enzyme-linked immuosorbent assay. The cell-signaling pathway was analyzed by means of Western blotting and gene silencing assays.
  
  
  RESULTS
  Streptococcus pneumoniae was significantly reduced from EM900-treated mice 14 days after pneumococcal inoculation. Macrophage recruitment and Ccl2 messenger RNA expression were promoted. CCL2 production from peritoneal macrophages was significantly induced by macrolides and was dependent on NF-κB phosphorylation through the myeloid differentiation primary-response gene 88- or TIR domain-containing adapter-inducing interferon-β-mediated pathway. Mortality of mice with invasive pneumococcal disease was improved by pretreatment with EM900.
  
  
  CONCLUSIONS
  Macrolides may inhibit invasive pneumococcal infections by accelerating the clearance of pneumococcal nasopharyngeal colonization via promotion of macrophage-mediated innate immunity.
authors.affiliation: Department of Respiratory Diseases.
authors.forename: Naoki
authors.initials: N
authors.lastname: Iwanaga
authors.affiliation: Department of Respiratory Diseases Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Respiratory Diseases.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oshima
authors.affiliation: Department of Respiratory Diseases.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kajihara
authors.affiliation: Department of Respiratory Diseases.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Takazono
authors.affiliation: Department of Respiratory Diseases.
authors.forename: Taiga
authors.initials: T
authors.lastname: Miyazaki
authors.affiliation: Department of Respiratory Diseases Unit of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences.
authors.forename: Koichi
authors.initials: K
authors.lastname: Izumikawa
authors.affiliation: Department of Laboratory Medicine, Nagasaki University Hospital.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yanagihara
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugawara
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
authors.affiliation: Kitasato Institute for Life Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.affiliation: Department of Respiratory Diseases.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000276:immunology / Q000494:pharmacology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D005260:Female; D007113:Immunity, Innate; D016899:Interferon-beta / Q000276:immunology; D018942:Macrolides / Q000276:immunology / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D009305:Nasopharynx / Q000382:microbiology*; D010587:Phagocytosis / Q000187:drug effects; D011008:Pneumococcal Infections / Q000276:immunology* / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D013047:Specific Pathogen-Free Organisms; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000276:immunology*
chemical_list: D000900:Anti-Bacterial Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018942:Macrolides; D016328:NF-kappa B; D016899:Interferon-beta
keywords: CCL2; Streptococcus pneumoniae; colonization; macrolides; macrophage