LL-37 and NET-Derived RNA Create a Self-Amplifying Inflammation Loop in Psoriasis
LL-37 combined with NET-derived RNA (not DNA) drives a self-propagating inflammatory cycle in psoriasis through TLR8/TLR13 signaling.
Quick Facts
What This Study Found
The study overturned a previous assumption. DNA was thought to be the key NET component driving inflammation in psoriasis. Instead, RNA is the critical molecule.
NET-associated RNA (naRNA), when complexed with LL-37, triggered both cytokine release and new NET formation by neutrophils through TLR8 (human) and TLR13 (mouse) receptors. This happened independently of the canonical NET component DNA.
The self-amplifying mechanism: activated neutrophils release NETs containing RNA. That RNA binds LL-37 (abundant in psoriatic skin). The complex activates more neutrophils to release more NETs with more RNA. Each cycle amplifies the inflammation.
Transferring NETs from activated neutrophils to naive (unstimulated) neutrophils triggered additional NET release, directly demonstrating the self-propagating nature of the cycle.
RNA was abundant in NETs and in psoriatic skin but not in healthy skin. This positions naRNA as a physiologically relevant NET component and a driver of chronic psoriatic inflammation.
Key Numbers
RNA not DNA is key; TLR8/TLR13 pathway; self-propagating NET cycle; LL-37 as essential partner; Nature Comms
How They Did This
Combined in vitro and in vivo study. Primary human and mouse neutrophils were used. NET formation, cytokine release, and TLR activation were measured. TLR8 and TLR13 dependency confirmed using receptor-specific approaches. NET transfer experiments demonstrated self-amplification. In vivo mouse models confirmed RNA-LL37 driven inflammation. RNA abundance compared between psoriatic and healthy skin.
Why This Research Matters
Psoriasis affects 2-3% of the global population with chronic skin inflammation. LL-37 was already known to be elevated in psoriatic skin. This study reveals the specific mechanism: LL-37 plus NET-derived RNA creates a self-sustaining inflammatory loop. Breaking this cycle could lead to new treatments. Published in Nature Communications, this is a high-impact mechanistic discovery.
The Bigger Picture
Psoriasis affects 2–3% of the global population. LL-37 was already known to be elevated in psoriatic skin, but this study identifies the specific molecular partnership (LL-37 + RNA) and pathway (TLR8) that creates runaway inflammation. Breaking this cycle could lead to targeted psoriasis treatments.
What This Study Doesn't Tell Us
Mouse and human TLR systems differ (TLR13 in mice, TLR8 in humans), which adds complexity to translating findings. The self-amplification was demonstrated in vitro and in mouse models, but whether this exact cycle operates in human psoriatic skin in vivo needs confirmation. The study does not show that blocking this pathway reduces psoriasis in a clinical setting.
Questions This Raises
- ?Would TLR8 inhibitors break the inflammatory cycle in psoriatic patients?
- ?Does this LL-37/RNA loop contribute to other inflammatory skin diseases?
- ?Can the NET-RNA source be specifically targeted without broadly suppressing immunity?
Trust & Context
- Key Stat:
- RNA, not DNA is the critical NET component that combines with LL-37 to create self-perpetuating inflammation in psoriasis
- Evidence Grade:
- Strong evidence from combined in vitro and in vivo studies published in Nature Communications. Mechanistic pathway clearly demonstrated.
- Study Age:
- Published in 2020 in Nature Communications. TLR8-targeted therapies for psoriasis are being explored.
- Original Title:
- Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis.
- Published In:
- Nature communications, 11(1), 105 (2020)
- Authors:
- Herster, Franziska, Bittner, Zsofia, Archer, Nathan K(3), Dickhöfer, Sabine, Eisel, David, Eigenbrod, Tatjana, Knorpp, Thomas, Schneiderhan-Marra, Nicole, Löffler, Markus W, Kalbacher, Hubert, Vierbuchen, Tim, Heine, Holger, Miller, Lloyd S, Hartl, Dominik, Freund, Lukas, Schäkel, Knut, Heister, Martin, Ghoreschi, Kamran, Weber, Alexander N R
- Database ID:
- RPEP-04852
Evidence Hierarchy
Frequently Asked Questions
What is the LL-37 inflammation loop in psoriasis?
LL-37 grabs RNA from dead neutrophils and presents it to immune receptors (TLR8). This triggers more inflammation, which attracts more neutrophils, which die and release more RNA — creating a vicious cycle that perpetuates psoriasis.
Could this lead to new psoriasis treatments?
Yes. Drugs that block TLR8 or prevent LL-37 from partnering with RNA could potentially break the inflammatory cycle. This is a more targeted approach than current broad immune suppression.
Read More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-04852APA
Herster, Franziska; Bittner, Zsofia; Archer, Nathan K; Dickhöfer, Sabine; Eisel, David; Eigenbrod, Tatjana; Knorpp, Thomas; Schneiderhan-Marra, Nicole; Löffler, Markus W; Kalbacher, Hubert; Vierbuchen, Tim; Heine, Holger; Miller, Lloyd S; Hartl, Dominik; Freund, Lukas; Schäkel, Knut; Heister, Martin; Ghoreschi, Kamran; Weber, Alexander N R. (2020). Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis.. Nature communications, 11(1), 105. https://doi.org/10.1038/s41467-019-13756-4
MLA
Herster, Franziska, et al. "Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis.." Nature communications, 2020. https://doi.org/10.1038/s41467-019-13756-4
RethinkPeptides
RethinkPeptides Research Database. "Neutrophil extracellular trap-associated RNA and LL37 enable..." RPEP-04852. Retrieved from https://rethinkpeptides.com/research/herster-2020-neutrophil-extracellular-trapassociated-rna
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.