Toll-like receptor 2/6 stimulation promotes angiogenesis via GM-CSF as a potential strategy for immune defense and tissue regeneration

Blood. 2010 Mar 25;115(12):2543-52. doi: 10.1182/blood-2009-05-224402. Epub 2010 Jan 7.


Toll-like receptors (TLRs) are known primarily as pathogen recognition receptors of the innate immunity, initiating inflammatory pathways to organize the immune defense. More recently, an involvement of TLRs in various physiologic and pathologic processes has been reported. Because many of these processes implicate angiogenesis, we here elucidated the role of a TLR2/6-dependent pathway on angiogenesis using the TLR2/6 agonist macrophage-activating lipopeptide of 2 kDa (MALP-2), a common bacterial lipopeptide. In vivo and in vitro Matrigel assays demonstrated that MALP-2 promoted angiogenesis in a TLR2/6-dependent manner. Moreover, MALP-2 induced endothelial cell proliferation and migration and a strong secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF release in response to MALP-2 from isolated vascular segments was completely prevented when the endothelium was removed. MALP-2 containing Matrigel implants exhibited vascular structures as well as CD45(+) cells. MALP-2 induced migration of leukocytes and likewise GM-CSF release, particularly from the monocyte population. Inhibition of GM-CSF by siRNA or antibodies suppressed MALP-2-induced angiogenesis in vitro and in vivo. These results clearly identified a TLR2/6-dependent induction of angiogenesis by the bacterial lipopeptide MALP-2, which is mediated by GM-CSF. This might represent a general mechanism to enhance or restore blood flow and recruit immune cells for pathogen defense and tissue regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Aorta / cytology
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cells, Cultured
  • Endothelial Cells / cytology
  • Endothelial Cells / immunology
  • Endothelial Cells / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / immunology
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Humans
  • Immune System / physiology
  • Leukocytes / cytology
  • Leukocytes / immunology
  • Leukocytes / metabolism
  • Lipopeptides / metabolism
  • Lipopeptides / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / physiology*
  • RNA, Small Interfering
  • Regeneration / physiology
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 6 / genetics
  • Toll-Like Receptor 6 / metabolism*
  • Umbilical Veins / cytology


  • Antibodies
  • Lipopeptides
  • RNA, Small Interfering
  • TLR2 protein, human
  • TLR6 protein, human
  • Tlr2 protein, mouse
  • Tlr6 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 6
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • macrophage stimulatory lipopeptide 2