The long non-coding RNA NEAT1 is overexpressed in rosacea skin and amplifies inflammation by regulating S100A9 expression through a mechanism triggered by the antimicrobial peptide LL-37.
237 differentially expressed lncRNAsFirst genome-wide lncRNA profiling of rosacea skin, with NEAT1 identified as a key driver linking cathelicidin peptide LL-37 to inflammatory gene expression
What the researchers found
RNA sequencing of skin from six rosacea patients identified 237 differentially expressed long non-coding RNAs, 38 miRNAs, and 1,784 mRNAs in lesioned vs. non-lesioned skin. NEAT1 was upregulated in both rosacea skin tissue and LL-37-treated HaCaT cells. Knocking down NEAT1 reduced inflammatory damage in vitro. NEAT1 directly interacted with miR-196a-5p, and downregulating miR-196a-5p reversed the anti-inflammatory effects of NEAT1 knockdown on S100A9, confirming the NEAT1/miR-196a-5p/S100A9 regulatory axis.
Why it matters
Rosacea affects millions of people and its molecular mechanisms are poorly understood, making treatment largely symptomatic. The cathelicidin peptide LL-37 has been identified as a key driver of rosacea inflammation, but how it triggers downstream inflammatory cascades was unclear. This study reveals a specific regulatory pathway (NEAT1/miR-196a-5p/S100A9) that connects LL-37 to sustained inflammation, providing potential new therapeutic targets that could interrupt the inflammatory cycle at its source.
How the study worked
Researchers performed genome-wide RNA sequencing on paired lesioned and non-lesioned skin samples from six rosacea patients, analyzing lncRNA, miRNA, and mRNA expression profiles. They identified hub lncRNAs in a competing endogenous RNA (ceRNA) network. In vitro experiments used HaCaT keratinocyte cells treated with the antimicrobial peptide LL-37 to model rosacea inflammation. Gene knockdown (siRNA) of NEAT1 and miR-196a-5p inhibitors were used to validate the regulatory axis.
What this study cannot tell us
The genomic profiling used only six patients, limiting statistical power and generalizability. The in vitro experiments used HaCaT cells (an immortalized keratinocyte line), which may not fully replicate the behavior of primary skin cells or the complex multicellular environment of rosacea skin. The study demonstrates association and a plausible mechanism but does not prove this axis drives rosacea in vivo. No therapeutic intervention was tested in animal models or patients.
How to read the evidence
This is an exploratory molecular study combining RNA sequencing from six patients with in vitro mechanistic validation. While the methodology is sound and the ceRNA network analysis is comprehensive, the small patient sample and lack of in vivo validation limit the strength of the evidence.
When this study was published
Published in 2021, this study is relatively recent. The connection between non-coding RNAs and peptide-mediated skin inflammation continues to be actively investigated.
The bigger picture
This study connects two important areas of dermatological research: the role of antimicrobial peptides (particularly cathelicidin/LL-37) in rosacea pathogenesis and the emerging field of non-coding RNA regulation in inflammatory skin diseases. The finding that LL-37 drives inflammation through a non-coding RNA cascade adds a new layer of complexity to our understanding of peptide-mediated skin inflammation and expands potential intervention points beyond targeting the peptide itself.
Questions still open
- Could targeting NEAT1 or the miR-196a-5p/S100A9 axis provide a new therapeutic approach for rosacea that is more targeted than current anti-inflammatory treatments?
- Is the NEAT1/miR-196a-5p/S100A9 axis active in all rosacea subtypes, or is it specific to certain clinical presentations?
- Do other antimicrobial peptides beyond LL-37 also trigger NEAT1 upregulation in inflammatory skin conditions?
Common questions
What does the antimicrobial peptide LL-37 have to do with rosacea?
What is a 'competing endogenous RNA' and how does it cause inflammation?
Read the original research
Long non-coding RNA NEAT1 functions as a competing endogenous RNA to regulate S100A9 expression by sponging miR-196a-5p in rosacea.
Journal of dermatological science, 102(1), 58-67
Citation
Wang, Lian; Wang, Yu-Jia; Hao, Dan; Wang, Xiao-Yun; Li, Xiao-Xue; Zhao, Qian; Li, Yan-Mei; He, Gu; Jiang, Xian. (2021). Long non-coding RNA NEAT1 functions as a competing endogenous RNA to regulate S100A9 expression by sponging miR-196a-5p in rosacea.. Journal of dermatological science, 102(1), 58-67. https://doi.org/10.1016/j.jdermsci.2021.02.005