Targeting the LL-37 Peptide Pathway Reduces Rosacea-Like Skin Inflammation in Mice | Research

The takeaway

An aryl hydrocarbon receptor agonist (benvitimod) ameliorated rosacea-like skin inflammation caused by the antimicrobial peptide LL-37 by suppressing TLR2 signaling and inflammatory chemokines in mice and skin cells.

Reduced redness and inflammation in 3 days
Topical benvitimod treatment significantly reduced redness scores, redness areas, and inflammatory cell infiltrates in mice with LL-37-induced rosacea-like eruptions after just 3 days of application.

What the researchers found

Topical benvitimod (1% and 0.5%) reduced redness scores, redness areas, and dermal inflammatory cell infiltrates in LL-37-induced rosacea-like eruptions in BALB/c mice. In both the mouse model and LL-37-treated HaCaT cells, AhR activation decreased elevated TLR2 expression and suppressed four inflammatory chemokines: CCL5, CXCL9, CXCL10, and CXCL11. Over-expressing TLR2 in HaCaT cells further enhanced chemokine release, confirming TLR2 as the key pathway. Benvitimod (10 μM) reduced gene expression at 8 hours and protein expression at 24 hours in LL-37-treated cells.

Why it matters

Rosacea affects over 400 million people worldwide and current treatments have limited efficacy. Understanding that LL-37 — an endogenous antimicrobial peptide — drives rosacea through TLR2 signaling provides a specific therapeutic target. This study shows AhR activation can block this peptide-driven inflammatory cascade, offering a mechanistically targeted treatment approach.

How the study worked

Female BALB/c mice received twice-daily intradermal LL-37 injections for 2 days to induce rosacea-like eruptions, then topical benvitimod (AhR agonist) at 0.5% or 1% for 3 days. Redness scores, areas, and histological inflammation were assessed. In vitro, HaCaT keratinocytes were treated with LL-37 and benvitimod, with TLR2 overexpression via lentivirus. Inflammatory markers (TLR2, CCL5, CXCL9, CXCL10, CXCL11) were measured by qRT-PCR, Western blot, and ELISA.

What this study cannot tell us

The LL-37 injection model creates acute rosacea-like symptoms that may not fully replicate the chronic nature of human rosacea. The study duration was very short (3 days of treatment). HaCaT cells are an immortalized keratinocyte line that may not perfectly represent primary skin cells. The AhR pathway has multiple effects beyond TLR suppression that weren't fully characterized. No human rosacea patients were studied. The relationship between LL-37 levels and specific rosacea subtypes was not addressed.

How to read the evidence

This is a preclinical study using a mouse model and cell culture. The LL-37 injection model is well-established for rosacea research, and the in vitro confirmation of the TLR2 pathway adds mechanistic strength. However, no human data were generated and the treatment duration was very short.

When this study was published

Published in 2022, this study addresses the growing understanding of LL-37's role in rosacea pathogenesis and explores a therapeutically actionable pathway.

The bigger picture

LL-37 plays a dual role in skin health — protective against infections but pathogenic in rosacea. This study highlights how endogenous peptides can cross from beneficial to harmful when overexpressed, and demonstrates that the downstream inflammatory cascade can be therapeutically interrupted. Benvitimod is already approved in China for psoriasis, making its repurposing for rosacea clinically feasible.

Questions still open

Would AhR activation with benvitimod be effective in human rosacea patients, particularly those with elevated LL-37 levels?
Could LL-37 levels serve as a biomarker to identify rosacea patients most likely to respond to AhR-targeted therapy?
What are the long-term effects of AhR activation on skin immunity, given that it suppresses both TLR2 and LL-37 signaling?

Common questions

How does LL-37 cause rosacea?

LL-37 is an antimicrobial peptide that normally protects your skin from infection. In rosacea patients, too much LL-37 is produced, which triggers an overactive inflammatory response through TLR2 receptors. This leads to the redness, swelling, and skin irritation characteristic of rosacea. Injecting LL-37 into mouse skin recreates these symptoms, confirming its role in the disease.

Could this lead to a new rosacea treatment?

Yes — this study shows that activating the aryl hydrocarbon receptor (AhR) with benvitimod blocks the inflammatory cascade triggered by LL-37. Since benvitimod is already approved for psoriasis in China, it could potentially be tested for rosacea relatively quickly. It would target the specific peptide-driven inflammation underlying rosacea, rather than just treating symptoms.

Read the original research

Activation of aryl hydrocarbon receptor ameliorates rosacea-like eruptions in mice and suppresses the TLR signaling pathway in LL-37-induced HaCaT cells.

Toxicology and applied pharmacology, 451, 116189

View on PubMed ↗Publisher’s paper ↗

Citation

Sun, Yan; Chen, LiangHong; Wang, HeXiao; Zhu, PeiYao; Jiang, ShiBin; Qi, RuiQun; Wu, Yan; Gao, XingHua. (2022). Activation of aryl hydrocarbon receptor ameliorates rosacea-like eruptions in mice and suppresses the TLR signaling pathway in LL-37-induced HaCaT cells.. Toxicology and applied pharmacology, 451, 116189. https://doi.org/10.1016/j.taap.2022.116189