Abstract
Psoriasis is an inflammatory skin disease with strong immune cell infiltration and high levels of the antimicrobial peptide, LL37. LL37 was shown to complex DNA and RNA to activate plasmacytoid dendritic cells (pDC) in vitro and this has been thought to drive interferon-mediated disease exacerbation. However, the physiological source of such nucleic acids and thus an early initiating event for nucleic-acid mediated inflammation remains unknown. We hypothesized that neutrophils (PMNs), which dominate the psoriatic skin infiltrate, may be the source of DNA and LL37 as well-established components of so-called neutrophil extracellular traps (NETs). We show here that indeed primary murine and human PMNs mount a fulminant NET and cytokine response, albeit not via DNA-but rather RNA-LL37 complexes. This was dependent on TLR8/TLR13 and sensitive to TLR inhibitory oligodeoxynucleotides. Unexpectedly, copious amounts of RNA were identified as a so far unappreciated NET component in vitro and in psoriatic but not healthy skin. Importantly, RNA-LL37-triggered NETs, when transferred to naïve PMNs, prompted additional de novo NET release. Our study highlights TLR-mediated RNA-LL37 sensing by PMNs as parts of a self-propagating vicious cycle that may later engulf pDC and establish chronic inflammation in psoriasis and NET-associated RNA (naRNA) as a physiologically relevant novel component.
Summary Human and bacterial RNA in complex with LL37 activates neutrophils via TLR8 to release cytokines, chemokines and neutrophil extracellular traps (NETs). NETs and neutrophil-rich areas in psoriatic skin contain immunostimulatory RNA, termed here NET-associated RNA (naRNA), and LL37, which may fuel a self-sustaining inflammatory cycle in psoriasis.
Footnotes
↵$ Change of address/additional addresses: David Eisel, GMP & T Cell Therapy Unit (G183), German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Abbreviations
- APC
- antigen-presenting cell
- bRNA
- bacterial ribonucleic acid
- EGFP
- Enhanced green fluorescence protein
- HEK
- Human embryonic kidney
- HLA
- Human leucocyte antigen
- iODN
- inhibitory oligonucleotides
- MAMPs
- Microbe-associated molecular pattern
- MHC
- Major histocompatibility complex
- iODNs
- Inhibitory oligodeoxynucleotides
- IFN
- Interferon
- IL
- Interleukin
- KC
- Keratinocytes
- PASI
- psoriasis area and severity
- pDCs
- Plasmacytoid dendritic cells
- PMA
- phorbol myristate acetate
- PRR
- Pattern recognition receptor
- PMNs
- Polymorphonuclear leukocytes
- NE
- Neutrophil elastase
- NET
- Neutrophil extracellular trap
- SEM
- Scanning electron microscopy
- SLE
- Systemic lupus erythematosus
- TLR
- Toll-like receptor
- TNF
- Tumor necrosis factor