How the Antimicrobial Peptide LL-37 Creates a Self-Fueling Inflammation Loop in Psoriasis | Research

The takeaway

LL-37 combined with RNA from immune cell traps creates a self-amplifying inflammatory signal that may drive psoriasis and other chronic inflammatory diseases.

Pre-stored in granules
The naRNA-LL37 inflammatory signal is pre-assembled inside resting neutrophils, ready to trigger a self-amplifying inflammation cycle upon release

What the researchers found

The antimicrobial peptide LL-37 and RNA from neutrophil extracellular traps (NETs) form a composite 'damage signal' (DAMP) that triggers a self-amplifying cycle of inflammation. This naRNA-LL37 complex stimulates fresh neutrophils to release more NETs via a TLR8–NLRP3 inflammasome pathway, and causes skin cells (keratinocytes) to express psoriasis-related genes (IL17, IL36) through NOD2-RIPK signaling.

Critically, the naRNA-LL37 DAMP is pre-stored in resting neutrophil granules — meaning it's ready to go before any infection occurs. In live mice, it drove temporary skin inflammation that was dramatically reduced when RNA-sensing was genetically eliminated. Under normal conditions, the signal is self-limiting, but when NET release is dysregulated (as in psoriasis), it creates a runaway inflammatory loop.

Why it matters

This study reveals a new mechanism by which the cathelicidin peptide LL-37 drives chronic inflammation in diseases like psoriasis, atherosclerosis, and arthritis. By showing that LL-37 complexed with RNA creates a self-amplifying inflammatory cycle, it identifies a potential therapeutic target — blocking RNA sensing could break the cycle and treat NET-driven inflammatory diseases.

The numbers in context

naRNA-LL37 is pre-stored in neutrophil granules · Signals via TLR8 + NLRP3 inflammasome · Keratinocyte activation via NOD2-RIPK · In vivo skin inflammation ablated by genetic knockout of RNA sensing

How the study worked

Multi-approach study combining in vitro experiments with human neutrophils and keratinocytes, and in vivo mouse models. Researchers characterized the naRNA-LL37 composite DAMP, identified signaling pathways (TLR8–NLRP3 in neutrophils, NOD2-RIPK in keratinocytes), demonstrated pre-storage in neutrophil granules, and used genetic ablation of RNA sensing in mice to confirm the pathway's role in skin inflammation.

Who was studied

In vitro human neutrophils and keratinocytes; in vivo mouse models of skin inflammation

What this study cannot tell us

Mouse models of skin inflammation may not fully recapitulate human psoriasis. The study demonstrates the pathway exists but doesn't quantify its relative contribution compared to other inflammatory drivers in psoriasis patients. Clinical translation — whether blocking RNA sensing would be safe and effective as a therapy — is not addressed.

How to read the evidence

This is a rigorous basic research study combining in vitro human cell experiments with in vivo mouse models and genetic validation. The multi-method approach provides strong mechanistic evidence, though clinical relevance in human disease remains to be confirmed.

When this study was published

Published in 2024 in EMBO Reports, this is a recent high-impact study that identifies a novel mechanism linking LL-37 to chronic inflammation — an active area of immunology research.

The bigger picture

LL-37 is the only cathelicidin antimicrobial peptide in humans and plays a dual role — fighting infections and modulating immunity. This study reveals a dark side: when dysregulated, LL-37 can fuel chronic inflammation by creating self-amplifying loops with NET-derived RNA. This connects LL-37 to the pathology of psoriasis, atherosclerosis, and arthritis, and identifies RNA sensing as a druggable intervention point in NET-driven inflammatory diseases.

Questions still open

Could drugs that block TLR8 or the NLRP3 inflammasome break the self-amplifying NET cycle and treat psoriasis?
Is the naRNA-LL37 DAMP elevated in psoriasis patient skin and blood compared to healthy controls?
Do other conditions driven by excessive NET formation (like lupus or COVID-related thrombosis) also involve this naRNA-LL37 self-amplification mechanism?

Common questions

What are neutrophil extracellular traps (NETs) and why do they cause problems?

NETs are web-like structures that neutrophils (immune cells) release to trap and kill bacteria. They're made of DNA, proteins, and antimicrobial peptides like LL-37. While they're effective against infection, excessive NET release can damage healthy tissue and drive chronic inflammation in conditions like psoriasis, arthritis, and blood vessel disease.

How does LL-37 contribute to psoriasis?

This study shows that LL-37, when combined with RNA from NETs, forms a signal that triggers more neutrophils to release more NETs — creating a vicious cycle. It also activates skin cells to produce psoriasis-related inflammatory molecules. Normally this cycle resolves on its own, but in psoriasis, it spins out of control, leading to chronic skin inflammation.

Read the original research

naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation.

EMBO reports, 25(7), 2914-2949

View on PubMed ↗Publisher’s paper ↗

Citation

Bork, Francesca; Greve, Carsten L; Youn, Christine; Chen, Sirui; N C Leal, Vinicius; Wang, Yu; Fischer, Berenice; Nasri, Masoud; Focken, Jule; Scheurer, Jasmin; Engels, Pujan; Dubbelaar, Marissa; Hipp, Katharina; Zalat, Baher; Szolek, Andras; Wu, Meng-Jen; Schittek, Birgit; Bugl, Stefanie; Kufer, Thomas A; Löffler, Markus W; Chamaillard, Mathias; Skokowa, Julia; Kramer, Daniela; Archer, Nathan K; Weber, Alexander N R. (2024). naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation.. EMBO reports, 25(7), 2914-2949. https://doi.org/10.1038/s44319-024-00150-5