Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis

Franziska Herster, Zsofia Bittner, Nathan K. Archer, Sabine Dickhöfer, David Eisel, Tatjana Eigenbrod, Thomas Knorpp, Nicole Schneiderhan-Marra, Markus W. Löffler, Hubert Kalbacher, Tim Vierbuchen, Holger Heine, Lloyd S. Miller, Dominik Hartl, Lukas Freund, Knut Schäkel, Martin Heister, Kamran Ghoreschi and Alexander N. R. Weber ()
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Franziska Herster: University of Tübingen
Zsofia Bittner: University of Tübingen
Nathan K. Archer: Johns Hopkins University School of Medicine
Sabine Dickhöfer: University of Tübingen
David Eisel: University of Tübingen
Tatjana Eigenbrod: University Hospital Heidelberg
Thomas Knorpp: NMI Natural and Medical Sciences Institute at the University of Tübingen
Nicole Schneiderhan-Marra: NMI Natural and Medical Sciences Institute at the University of Tübingen
Markus W. Löffler: University of Tübingen
Hubert Kalbacher: Interfaculty Institute of Biochemistry, University of Tübingen
Tim Vierbuchen: Research Group Innate Immunity, Research Center Borstel, Leibniz Lung Center, Airway Research Center North (ARCN), Deutsches Zentrum für Lungenforschung (DZL)
Holger Heine: Research Group Innate Immunity, Research Center Borstel, Leibniz Lung Center, Airway Research Center North (ARCN), Deutsches Zentrum für Lungenforschung (DZL)
Lloyd S. Miller: Johns Hopkins University School of Medicine
Dominik Hartl: University Children’s Hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen
Lukas Freund: University Hospital Heidelberg
Knut Schäkel: University Hospital Heidelberg
Martin Heister: University Hospital Tübingen
Kamran Ghoreschi: University Hospital Tübingen
Alexander N. R. Weber: University of Tübingen

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13756-4

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