Cathelicidin LL37 and mTORC1 Form a Feedback Loop That Drives Rosacea | Research

The takeaway

The antimicrobial peptide cathelicidin LL37 activates mTORC1 signaling via TLR2, which in turn increases cathelicidin expression, creating a positive feedback loop that drives rosacea skin inflammation — potentially treatable with rapamycin.

Positive feedback loop identified
LL37→TLR2→mTORC1→more cathelicidin — explaining why rosacea inflammation persists and recurs

What the researchers found

Cathelicidin LL37 activates mTORC1 via TLR2, and mTORC1 increases cathelicidin expression, creating a positive feedback loop driving rosacea. Topical rapamycin broke this cycle and improved patient symptoms.

Why it matters

Rosacea affects millions with limited treatment options. Identifying a specific molecular loop that perpetuates the disease — and showing that an existing drug (rapamycin) can break it — provides both mechanistic understanding and a immediately actionable therapeutic approach.

The numbers in context

mTORC1 hyperactivation in rosacea epidermis; topical rapamycin improved clinical symptoms; LL37 activates mTORC1 via TLR2

How the study worked

Human rosacea skin biopsies. LL37-induced mouse rosacea model. Epithelium-specific mTORC1 knockout and hyperactivation. mTORC1 inhibitor treatment. NF-κB activation and cytokine profiling. Clinical application of topical rapamycin in rosacea patients.

Who was studied

Rosacea patients and LL37-induced rosacea mouse model

What this study cannot tell us

Mouse rosacea model uses exogenous LL37 injection which may not perfectly replicate spontaneous human disease. Clinical rapamycin data appears preliminary. Long-term safety of topical rapamycin for rosacea not established.

How to read the evidence

Published in EMBO Molecular Medicine with human tissue validation, genetic mouse models, and clinical rapamycin application. High-quality translational evidence.

When this study was published

Published in 2021, providing a mechanistic breakthrough for understanding rosacea pathogenesis.

The bigger picture

Cathelicidin LL37 was previously known to be elevated in rosacea, but why it stays elevated was unclear. This study reveals the self-perpetuating mechanism — a positive feedback loop with mTORC1 — explaining the chronic relapsing nature of rosacea and providing a rational drug target.

Questions still open

Would topical rapamycin provide sustained rosacea improvement long-term?
Are there more specific mTORC1 pathway targets that could avoid rapamycin's immunosuppressive effects?
Does this feedback loop vary across rosacea subtypes?

Common questions

Why does rosacea keep coming back?

This study found that rosacea is driven by a self-amplifying feedback loop. The antimicrobial peptide cathelicidin LL37 activates mTORC1 signaling, which then produces more cathelicidin, which activates more mTORC1 — creating a vicious cycle that perpetuates inflammation.

Could rapamycin treat rosacea?

Early results look promising. Topical rapamycin breaks the cathelicidin-mTORC1 feedback loop and improved rosacea symptoms in patients in this study. Rapamycin is already FDA-approved for other uses, which could accelerate its development for rosacea if larger trials confirm these findings.

Read the original research

A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea.

EMBO molecular medicine, 13(5), e13560

View on PubMed ↗Publisher’s paper ↗

Citation

Deng, Zhili; Chen, Mengting; Liu, Yingzi; Xu, San; Ouyang, Yuyan; Shi, Wei; Jian, Dan; Wang, Ben; Liu, Fangfen; Li, Jinmao; Shi, Qian; Peng, Qinqin; Sha, Ke; Xiao, Wenqin; Liu, Tangxiele; Zhang, Yiya; Zhang, Hongbing; Wang, Qian; Sun, Lunquan; Xie, Hongfu; Li, Ji. (2021). A positive feedback loop between mTORC1 and cathelicidin promotes skin inflammation in rosacea.. EMBO molecular medicine, 13(5), e13560. https://doi.org/10.15252/emmm.202013560