LL-37 Antimicrobial Peptide Accelerates Wound Healing in Diabetic Mice

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.

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.

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.

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.