The human antimicrobial peptide LL-37 activated skin cell migration through multiple signaling pathways and significantly improved wound healing in diabetic mice when delivered by gene therapy.
Dual-action peptideLL-37 both fights wound infections (antimicrobial) and accelerates healing (cell migration, tissue formation) — working in diabetic mice where healing is most impaired
What the researchers found
LL-37 activated migration of HaCaT human keratinocytes through multiple mechanisms: phenotypic changes in actin dynamics, increased tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin, induction of Snail and Slug transcription factors (associated with cell motility), activation of matrix metalloproteinases, and engagement of MAPK and PI3K/Akt signaling pathways.
These effects were mediated through both EGFR transactivation and induction of the FPRL-1 G-protein-coupled receptor. In vivo, adenoviral delivery of LL-37 to excisional wounds in ob/ob diabetic mice significantly improved re-epithelialization and granulation tissue formation — demonstrating that LL-37's wound healing benefits translate from cell culture to a clinically relevant impaired-healing animal model.
Why it matters
Chronic non-healing wounds — particularly diabetic ulcers — affect millions of people worldwide and are a leading cause of amputation. Current wound treatments are often inadequate. LL-37's unique dual action as both an antimicrobial agent (fighting wound infections) and a wound healing promoter (stimulating skin cell migration and tissue repair) makes it an exceptionally promising therapeutic candidate. The fact that it worked in diabetic mice, which have the most challenging healing environment, is particularly encouraging.
How the study worked
In vitro experiments used HaCaT human keratinocytes to characterize LL-37's effects on cell migration, actin dynamics, focal adhesion signaling, transcription factor expression, metalloproteinase activation, and signaling pathway engagement (MAPK, PI3K/Akt, EGFR, FPRL-1). In vivo experiments used adenoviral transfer to deliver LL-37 to excisional wounds in ob/ob mice (a model of diabetic impaired wound healing). Wound healing was assessed by measuring re-epithelialization and granulation tissue formation.
What this study cannot tell us
The in vitro work used an immortalized keratinocyte cell line (HaCaT) which may not fully represent primary human skin cells. The in vivo delivery used adenoviral gene transfer, which is not a practical clinical delivery method for routine wound care. The ob/ob mouse model, while useful for studying impaired healing, has a specific genetic obesity that differs from most human diabetic wounds. The study did not assess long-term wound outcomes or scar quality. The multiple signaling pathways identified may not all contribute equally to the healing effect in vivo.
How to read the evidence
This study combines detailed in vitro mechanistic work with in vivo proof-of-concept in a diabetic wound model. While the evidence is strong for a preclinical study, the adenoviral delivery method is not clinically translatable, and human wound healing trials would be needed.
When this study was published
Published in 2008 in the Journal of Investigative Dermatology, this is a highly cited foundational study in LL-37 wound healing research. Its signaling pathway findings have been confirmed and expanded by subsequent research over the following 17 years.
The bigger picture
This study was a landmark in establishing LL-37 as more than just an antimicrobial peptide. Published in the Journal of Investigative Dermatology, it demonstrated that the body's innate defense peptide has a second, independent role in tissue repair. The detailed signaling pathway mapping (EGFR transactivation, Snail/Slug induction, MMP activation) connected LL-37's wound healing effects to pathways already known to be critical in wound repair — suggesting it activates the same programs that the body normally uses to close wounds, but can boost them when natural healing is impaired.
Questions still open
- Could topical LL-37 formulations (creams or gels) be developed for practical clinical use in chronic wound care?
- Does LL-37's dual antimicrobial and wound healing activity make it superior to existing wound treatments that only address one of these functions?
- Would LL-37 wound treatment reduce the rate of diabetic foot amputations in clinical trials?
Common questions
How does LL-37 help wounds heal if it's known as an antimicrobial peptide?
Why is diabetic wound healing so difficult, and could LL-37 help?
Read the original research
In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37.
The Journal of investigative dermatology, 128(1), 223-36
Citation
Carretero, Marta; Escámez, María J; García, Marta; Duarte, Blanca; Holguín, Almudena; Retamosa, Luisa; Jorcano, Jose L; Río, Marcela Del; Larcher, Fernando. (2008). In vitro and in vivo wound healing-promoting activities of human cathelicidin LL-37.. The Journal of investigative dermatology, 128(1), 223-36.