DNA-release by Streptococcus pneumoniae autolysin LytA induced Krueppel-like factor 4 expression in macrophages

Sci Rep. 2018 Apr 10;8(1):5723. doi: 10.1038/s41598-018-24152-1.


The recruitment of myeloid cells to the lung is of utmost importance for the elimination of invading pathogens. We investigated the Streptococcus pneumoniae-dependent induction mechanism of KLF4 in macrophages as a potential regulator of the macrophage immune response. We demonstrated that only viable pneumococci, which have direct contact to the host cells and release LytA-dependent DNA, induced KLF4. Exogenous supplementation of pneumococcal, other bacterial, eukaryotic foreign (human) or self (mouse) DNA to autolysis-deficient pneumococci restored (at least in part) pneumococci-related KLF4 induction. Experiments using TLR9, TRIF and MyD88 knockout macrophages revealed that TLR9, TRIF and MyD88 were partly involved in the S. pneumoniae-induced KLF4 expression. BMMs missing important DNA receptor related molecules (ASC-/-, STING-/-) showed no differences in pneumococci-related KLF4 expression. Similar results were observed with IFNAR-/- BMMs and Type I IFN stimulated cells. LyzMcre mediated knockdown of KLF4 in BMMs resulted in a decreased secretion of proinflammatory cytokines and enhanced IL-10 release. In summary, we showed that pneumococci-related KLF4 induction in macrophages is mediated via a PAMP-DAMP induction mechanism involving a hitherto unknown host cell DNA sensor leading to a more proinflammatory macrophage phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Autocrine Communication
  • Bacterial Capsules / immunology
  • Cytokines / metabolism
  • DNA, Bacterial / metabolism*
  • Gene Expression Regulation
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Humans
  • Inflammation Mediators / metabolism
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors / genetics*
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Mice
  • N-Acetylmuramoyl-L-alanine Amidase / metabolism*
  • Paracrine Communication
  • Phagocytosis / immunology
  • Pneumococcal Infections / genetics*
  • Pneumococcal Infections / immunology
  • Pneumococcal Infections / microbiology*
  • Streptococcus pneumoniae / physiology*
  • Toll-Like Receptor 9 / metabolism


  • Adaptor Proteins, Vesicular Transport
  • Cytokines
  • DNA, Bacterial
  • Inflammation Mediators
  • KLF4 protein, human
  • Klf4 protein, mouse
  • Kruppel-Like Factor 4
  • Kruppel-Like Transcription Factors
  • TICAM-1 protein, mouse
  • Toll-Like Receptor 9
  • N-Acetylmuramoyl-L-alanine Amidase