C-type Lectin Mincle Recognizes Glucosyl-diacylglycerol of Streptococcus pneumoniae and Plays a Protective Role in Pneumococcal Pneumonia

PLoS Pathog. 2016 Dec 6;12(12):e1006038. doi: 10.1371/journal.ppat.1006038. eCollection 2016 Dec.

Abstract

Among various innate immune receptor families, the role of C-type lectin receptors (CLRs) in lung protective immunity against Streptococcus pneumoniae (S. pneumoniae) is not fully defined. We here show that Mincle gene expression was induced in alveolar macrophages and neutrophils in bronchoalveolar lavage fluids of mice and patients with pneumococcal pneumonia. Moreover, S. pneumoniae directly triggered Mincle reporter cell activation in vitro via its glycolipid glucosyl-diacylglycerol (Glc-DAG), which was identified as the ligand recognized by Mincle. Purified Glc-DAG triggered Mincle reporter cell activation and stimulated inflammatory cytokine release by human alveolar macrophages and alveolar macrophages from WT but not Mincle KO mice. Mincle deficiency led to increased bacterial loads and decreased survival together with strongly dysregulated cytokine responses in mice challenged with focal pneumonia inducing S. pneumoniae, all of which was normalized in Mincle KO mice reconstituted with a WT hematopoietic system. In conclusion, the Mincle-Glc-DAG axis is a hitherto unrecognized element of lung protective immunity against focal pneumonia induced by S. pneumoniae.

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid
  • Flow Cytometry
  • Glycolipids / immunology
  • Glycolipids / metabolism*
  • Humans
  • Immunophenotyping
  • Lectins, C-Type / immunology*
  • Lectins, C-Type / metabolism
  • Macrophages, Alveolar / immunology*
  • Membrane Proteins / immunology
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / immunology
  • Pneumonia, Pneumococcal / immunology*
  • Real-Time Polymerase Chain Reaction
  • Receptors, Immunologic / immunology*
  • Receptors, Immunologic / metabolism
  • Streptococcus pneumoniae / immunology*
  • Streptococcus pneumoniae / metabolism

Substances

  • CLEC4D protein, human
  • Clecsf8 protein, mouse
  • Glycolipids
  • Lectins, C-Type
  • Membrane Proteins
  • Receptors, Immunologic
  • glucosyl diacylglycerol

Grant support

TW and UAM have been funded by the Federal Ministry of Education and Research (https://www.bmbf.de/en/index.html) in support of the German Center for Lung Research DZL to perform the current study. SY has been supported by Grant-in-Aid for Scientific Research (26293099 and 26110009) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and Grants from the Ministry of Health, Labour and Welfare (MHLW), and the Research on Development of New Drugs, AMED. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.