Abstract
Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor–like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis.
Highlights
Antimicrobial peptides are effector molecules of the innate immune system with microbicidal and proinflammatory activities [1, 2]
Human umbilical vein endothelial cells (HUVECs; 104) [17] seeded on six-well plastic dishes were stimulated with the following substances in different concentrations: LL-37 (37 C-terminal amino acids), WKYMVm (W peptide) (500 ng/ml; Humboldt University, Berlin, Germany), VEGF165 (5 ng/ml; Sigma-Aldrich Chemie GmbH, Munich, Germany), a scrambled version of LL-37 called sLL-37 (RSLEGTDRFPFVRLKNSRKLEFKDIKGIKREQFVKIL), hBD-3 synthesized as described earlier [18], human α-defensins isolated from neutrophil granules as a mixture of human neutrophil peptide–1 (HNP-1), -2, and -3, as described previously [19], and the recombinant hCAP-18 [20]
When the peptide was applied in the chorioallantoic membrane (CAM) assay, a model for physiologic angiogenesis, a significant induction of vessel growth was observed at doses of 5 μg/pellet (Figure 1, a–c)
Summary
Antimicrobial peptides are effector molecules of the innate immune system with microbicidal and proinflammatory activities [1, 2]. Cathelicidins are one family of antimicrobial peptides characterized by conserved propeptide sequences that were identified in several mammalian species. LL-37/hCAP-18 is the only antimicrobial peptide of the cathelicidin family iden-. Mice with disrupted Cnlp, the gene coding for CRAMP (cathelinrelated antimicrobial peptide), showed increased susceptibility to skin infections with group A Streptococcus [12]. Cathelicidin antimicrobial peptides seem to play a central role in host defense by direct antimicrobial activity and modulation of inflammation. The role of antimicrobial peptides as effector molecules of innate immunity is widening from solely endogenous antibiotics to multifunctional mediators that provide a first line of host defense, modify the local inflammatory response, and activate adaptive immunity
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