Leukocyte attraction by CCL20 and its receptor CCR6 in humans and mice with pneumococcal meningitis

PLoS One. 2014 Apr 3;9(4):e93057. doi: 10.1371/journal.pone.0093057. eCollection 2014.

Abstract

We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Blotting, Western
  • Brain / immunology*
  • Brain / metabolism
  • Brain / microbiology
  • Case-Control Studies
  • Cells, Cultured
  • Chemokine CCL20 / antagonists & inhibitors
  • Chemokine CCL20 / immunology
  • Chemokine CCL20 / metabolism*
  • Chemotaxis, Leukocyte / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Humans
  • Immunoenzyme Techniques
  • Male
  • Meningitis, Pneumococcal / cerebrospinal fluid
  • Meningitis, Pneumococcal / immunology*
  • Meningitis, Pneumococcal / metabolism
  • Meningitis, Pneumococcal / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prognosis
  • Prospective Studies
  • Receptors, CCR6 / physiology*
  • Survival Rate
  • Tumor Cells, Cultured

Substances

  • Antibodies, Monoclonal
  • Chemokine CCL20
  • Receptors, CCR6

Grant support

The financial aid of the Meningitis Research Foundation (MRF), the Deutsche Forschungsgemeinschaft (DFG), the University of Munich (FöFoLe), the Friedrich Baur Stiftung, and the Else Kroener Fresenius Foundation (EKFS) to M.K., U.K., and H.W.P. is highly appreciated. Also, the authors thank the American Lebanese Syrian Associated Charities (ALSAC) for support of H.H. The support from the Netherlands Organization for Health Research and Development (ZonMw NWO-Veni grant 2006 [916.76.023] and ZonMw NWO406 Vidi grant 2010 [917.11.358], both to D.B.), the Academic Medical Center (AMC Fellowship 2008 to D.B.), and European Research Council (ERC Starting Grant [281156] to D.B.) are appreciated. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.