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Nat Commun. 2020 Jan 8;11(1):105. doi: 10.1038/s41467-019-13756-4.

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

Author information

1
Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany.
2
Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
3
David Eisel, BioNTech, An der Goldgrube 12, 55131, Mainz, Germany.
4
Department of Infectious Diseases, Medical Microbiology and Hygiene, University Hospital Heidelberg, Im Neuenheimer Feld 324, 69120, Heidelberg, Germany.
5
NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany.
6
Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
7
Department of Clinical Pharmacology, University Hospital Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
8
Interfaculty Institute of Biochemistry, University of Tübingen, Hoppe-Seyler-Str. 4, 72076, Tübingen, Germany.
9
Research Group Innate Immunity, Research Center Borstel, Leibniz Lung Center, Airway Research Center North (ARCN), Deutsches Zentrum für Lungenforschung (DZL), Parkallee 22, 23845, Borstel, Germany.
10
University Children's Hospital and Interdisciplinary Center for Infectious Diseases, University of Tübingen, Hoppe-Seyler-Str. 1, 72076, Tübingen, Germany.
11
Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.
12
Department of Dermatology, University Hospital Heidelberg, Im Neuenheimer Feld 440, 69120, Heidelberg, Germany.
13
Department of Dermatology, University Hospital Tübingen, Liebermeisterstr. 25, 72076, Tübingen, Germany.
14
Department of Dermatology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
15
Department of Immunology, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany. alexander.weber@uni-tuebingen.de.

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.

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