Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis
Franziska Herster1, Zsofia Bittner1, Nathan K Archer2
1Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany.
Abstract:
Psoriasis is an inflammatory skin disease with strong neutrophil (PMN) infiltration and high levels of the antimicrobial peptide, LL37. LL37 in complex with DNA and RNA is thought to initiate disease exacerbation via plasmacytoid dendritic cells. However, the source of nucleic acids supposed to start this initial inflammatory event remains unknown. We show here that primary murine and human PMNs mount a fulminant and self-propagating neutrophil extracellular trap (NET) and cytokine response, but independently of the canonical NET component, DNA. Unexpectedly, RNA, which is abundant in NETs and psoriatic but not healthy skin, in complex with LL37 triggered TLR8/TLR13-mediated cytokine and NET release by PMNs in vitro and in vivo. Transfer of NETs to naive human PMNs prompts additional NET release, promoting further inflammation. Our study thus uncovers a self-propagating vicious cycle contributing to chronic inflammation in psoriasis, and NET-associated RNA (naRNA) as a physiologically relevant NET component.
Insights
Psoriasis inflammation involves neutrophils releasing neutrophil extracellular traps (NETs). NET-associated RNA (naRNA) complexed with LL37 triggers a self-propagating inflammatory cycle, independent of DNA, driving chronic skin disease.
Area of Science:
- Immunology
- Dermatology
- Molecular Biology
Background:
- Psoriasis is an inflammatory skin condition characterized by neutrophil infiltration and LL37.
- LL37 complexed with nucleic acids is implicated in disease exacerbation, but the nucleic acid source is unknown.
- Neutrophil extracellular traps (NETs) are a key feature of psoriasis.
Purpose of the Study:
- To investigate the role of nucleic acids in psoriasis-driven inflammation.
- To identify the source and function of nucleic acids within NETs in psoriasis.
- To elucidate the mechanism of self-propagating inflammation in psoriasis.
Main Methods:
- Analysis of primary murine and human neutrophils.
- In vitro and in vivo experiments assessing cytokine and NET release.
- Investigation of Toll-like receptor (TLR) involvement.
Main Results:
- Neutrophils mount a self-propagating response involving NETs and cytokines, independent of DNA.
- NET-associated RNA (naRNA), not DNA, complexed with LL37 triggers TLR8/TLR13-mediated inflammation.
- Psoriatic skin contains abundant naRNA, unlike healthy skin.
- Transfer of NETs induces further NET release and inflammation.
Conclusions:
- NET-associated RNA (naRNA) is a key driver of psoriasis inflammation.
- A self-propagating cycle of naRNA-LL37 complex-mediated NETosis contributes to chronic inflammation in psoriasis.
- Targeting naRNA may offer a novel therapeutic strategy for psoriasis.
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