How LL-37 and Damage Signals Team Up to Trigger Skin Repair Growth Factors

What the researchers found

Double-stranded RNA acting as a damage signal significantly increased expression of multiple growth factors in keratinocytes, endothelial cells, and fibroblasts. When LL-37 was added alongside dsRNA — mimicking real wound conditions — RNA sequencing revealed even greater growth factor upregulation.

Specifically, keratinocytes exposed to both LL-37 and dsRNA showed increased expression of FGF2 (basic fibroblast growth factor), HBEGF (heparin-binding EGF-like growth factor), VEGFC (vascular endothelial growth factor C), betacellulin, EGF, epiregulin, and members of the TGF-β superfamily. These results were validated by quantitative PCR and ELISA, confirming that antimicrobial peptides play a direct role in stimulating tissue repair — not just fighting infection.

Why it matters

This study reveals that LL-37 does more than kill bacteria — it actively promotes wound healing by amplifying growth factor production. Understanding this dual role could lead to new wound-healing therapies that harness the body's own antimicrobial peptides to accelerate skin repair, particularly for chronic wounds that fail to heal normally.

How the study worked

Researchers exposed cultured human keratinocytes, endothelial cells, and fibroblasts to double-stranded RNA alone or combined with LL-37 peptide. They used RNA sequencing to map the full transcriptome response, then confirmed key findings with quantitative PCR and ELISA protein assays. The combined treatment was designed to mimic the molecular environment of a real skin wound.

What this study cannot tell us

This was an in vitro study using cultured cells, so the results may not fully translate to living tissue. The study did not test specific dose-response relationships for LL-37 or measure how long the growth factor boost lasted. No animal or human wound models were used to confirm these effects in a real healing environment.

How to read the evidence

This is a laboratory (in vitro) study using cultured human cells. While it provides mechanistic insight into how LL-37 affects growth factor expression, the findings have not been validated in animal models or human clinical trials, placing it at a preclinical evidence level.

When this study was published

Published in 2016, this study is about 10 years old. The fundamental findings about LL-37 and growth factor signaling remain relevant, as subsequent research has continued to explore cathelicidins in wound healing contexts.

The bigger picture

LL-37 is the only cathelicidin antimicrobial peptide in humans, and most research has focused on its bacteria-killing properties. This study expands our understanding by showing it also orchestrates tissue repair through growth factor signaling. This connects to the broader field of wound healing research and suggests antimicrobial peptides could be therapeutic tools for promoting skin regeneration, not just fighting infection.

Questions still open

• Could topical LL-37 application accelerate wound healing in chronic non-healing wounds?
• What is the optimal concentration of LL-37 needed to maximize growth factor production without triggering excessive inflammation?
• Do other antimicrobial peptides besides LL-37 have similar growth factor-stimulating effects?

Common questions

Read the original research

Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells.

The Journal of biological chemistry, 291(22), 11635-46

Citation

Adase, Christopher A; Borkowski, Andrew W; Zhang, Ling-Juan; Williams, Michael R; Sato, Emi; Sanford, James A; Gallo, Richard L. (2016). Non-coding Double-stranded RNA and Antimicrobial Peptide LL-37 Induce Growth Factor Expression from Keratinocytes and Endothelial Cells.. The Journal of biological chemistry, 291(22), 11635-46. https://doi.org/10.1074/jbc.M116.725317