In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37.
The human antimicrobial peptide LL-37 plays an important role in host defense against infection. In addition to its antimicrobial action, other activities have been described in eukaryotic cells that may contribute to the healing response. In this study, we demonstrated that in vitro human cathelicidin activates migration of the human keratinocyte cell line HaCaT, involving phenotypic changes related to actin dynamics and associated to augmented tyrosine phosphorylation of proteins involved in focal adhesion complexes, such as focal adhesion kinase and paxillin. Other events involved in the LL-37 response were the induction of the Snail and Slug transcription factors, activation of matrix metalloproteinases and activation of the mitogen-activated protein kinase , and phosphoinositide 3-kinase/Akt signaling pathways. These signaling events could be mediated not only through the transactivation of EGFR but also through the induction of G-protein-coupled receptor FPRL-1 expression in these cells. Finally, by in vivo adenoviral transfer of the antimicrobial peptide to excisional wounds in ob/ob mice, we demonstrated that LL-37 significantly improved re-epithelialization and granulation tissue formation. The protective and regenerative activities of LL-37 support its therapeutic potential to promote wound healing.
Carretero
Marta
M
Regenerative Medicine Unit, Epithelial Biomedicine Division, Basic Research Department, CIEMAT-CIBERER, Madrid, Spain.
Escámez
María J
MJ
García
Marta
M
Duarte
Blanca
B
Holguín
Almudena
A
Retamosa
Luisa
L
Jorcano
Jose L
JL
Río
Marcela Del
MD
Larcher
Fernando
F
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000502:physiology*; D054804:Cathelicidins; D002460:Cell Line; D002465:Cell Movement; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D004848:Epithelium / Q000502:physiology; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D022001:Focal Adhesions; D006097:Granulation Tissue / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000502:physiology; D044067:Receptors, Lipoxin / Q000235:genetics / Q000502:physiology; D012038:Regeneration; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000502:physiology; D014945:Wound Healing