How Ivermectin Treats Rosacea: It Blocks the Antimicrobial Peptide LL-37 That Drives Inflammation | Research

The takeaway

Ivermectin cream treats rosacea by inhibiting the enzyme KLK5 and reducing production of the cathelicidin peptide LL-37, which when overproduced drives the facial inflammation characteristic of rosacea.

KLK5 + LL-37 pathway blocked
Ivermectin inhibited both the enzyme (KLK5) and antimicrobial peptide (LL-37) overproduction that drives rosacea inflammation

What the researchers found

Ivermectin inhibited KLK5 and CAMP (cathelicidin) gene expression and protein secretion in normal human epidermal keratinocytes (NHEK) stimulated with calcitriol. These results were confirmed in two 3D skin models — reconstructed human epidermis (RHE) and human skin ex vivo.

The anti-inflammatory effects extended beyond the cathelicidin pathway: ivermectin also reduced secretion of inflammatory cytokines IL-8, IL-6, and the chemokine MCP-1 (CCL2). This demonstrates that ivermectin targets the upstream molecular drivers of rosacea inflammation rather than just masking symptoms.

Why it matters

Rosacea affects millions of people and can significantly impact quality of life. Ivermectin cream is FDA-approved for rosacea but was originally an anti-parasitic drug — understanding that it works by modulating the antimicrobial peptide LL-37 provides a rational basis for its use and could inspire development of more targeted treatments that specifically address the cathelicidin/KLK5 pathway.

How the study worked

Three experimental systems were used: (1) normal human epidermal keratinocytes (NHEK) in 2D culture, (2) reconstructed human epidermis (RHE, a 3D skin model), and (3) human skin ex vivo. All models were stimulated with calcitriol (vitamin D3 metabolite) to induce KLK5 and LL-37 expression, mimicking rosacea conditions. Gene expression, protein secretion, and inflammatory cytokine levels were measured after ivermectin treatment.

What this study cannot tell us

All experiments were performed in vitro or ex vivo — no clinical trial data are presented. The calcitriol stimulation model approximates but does not fully replicate the complex pathophysiology of rosacea in living patients. The study was funded by Nestlé Skin Health R&D (which markets ivermectin cream), representing a potential conflict of interest. Specific concentrations of ivermectin used are not detailed in the abstract.

How to read the evidence

This is a mechanistic in vitro/ex vivo study using multiple skin models. It provides strong evidence for ivermectin's mechanism of action but does not include clinical outcome data.

When this study was published

Published in 2017, this study helped establish the mechanistic rationale for ivermectin's use in rosacea, which had been approved based on clinical efficacy without a fully understood mechanism.

The bigger picture

LL-37 is one of the most studied human antimicrobial peptides, normally playing a protective role in skin defense. But its overexpression is implicated in rosacea, psoriasis, and other inflammatory skin conditions. This study connects peptide biology with clinical dermatology, showing that modulating antimicrobial peptide levels can be a viable therapeutic strategy. It also highlights the dual nature of host defense peptides — beneficial in infection, harmful when dysregulated.

Questions still open

Could drugs targeting KLK5 more specifically than ivermectin provide even better rosacea treatment with fewer side effects?
Does the LL-37 reduction seen in skin models correlate with the degree of clinical improvement seen in rosacea patients?
Are there subtypes of rosacea patients who have higher LL-37/KLK5 levels and would respond better to ivermectin?

Common questions

What is LL-37 and why does it cause problems in rosacea?

LL-37 is a human antimicrobial peptide that normally helps protect skin from infection. In rosacea, the skin produces too much LL-37, which triggers excessive inflammation, blood vessel dilation, and the characteristic redness and bumps. The enzyme KLK5 processes the precursor protein cathelicidin into active LL-37, so blocking KLK5 reduces LL-37 production.

Isn't ivermectin mainly used for parasites? How does it help a skin condition?

Ivermectin was originally developed as an anti-parasitic drug, and it may partly help rosacea by killing Demodex mites that live in facial skin. But this study shows it has a separate anti-inflammatory mechanism — directly blocking the overproduction of the peptide LL-37 that drives rosacea inflammation. This dual action (anti-parasitic and anti-inflammatory) may explain why it is so effective for rosacea.

Read the original research

Topical Treatment of Rosacea with Ivermectin Inhibits Gene Expression of Cathelicidin Innate Immune Mediators, LL-37 and KLK5, in Reconstructed and Ex Vivo Skin Models.

Dermatology and therapy, 7(2), 213-225

View on PubMed ↗Publisher’s paper ↗

Citation

Thibaut de Ménonville, Séverine; Rosignoli, Carine; Soares, Estelle; Roquet, Manon; Bertino, Béatrice; Chappuis, Jean-Paul; Defoin-Platel/Chaussade, Claire; Piwnica, David. (2017). Topical Treatment of Rosacea with Ivermectin Inhibits Gene Expression of Cathelicidin Innate Immune Mediators, LL-37 and KLK5, in Reconstructed and Ex Vivo Skin Models.. Dermatology and therapy, 7(2), 213-225. https://doi.org/10.1007/s13555-017-0176-3