2. Academic Validation
  3. naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation

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

  • EMBO Rep. 2024 May 23. doi: 10.1038/s44319-024-00150-5.
Francesca Bork 1,  Carsten L Greve 1,  Christine Youn 2,  Sirui Chen 1,  Vinicius N C Leal 1 3,  Yu Wang 2,  Berenice Fischer 4,  Masoud Nasri 5,  Jule Focken 6,  Jasmin Scheurer 6,  Pujan Engels 1,  Marissa Dubbelaar 7 8,  Katharina Hipp 9,  Baher Zalat 1,  Andras Szolek 1,  Meng-Jen Wu 2,  Birgit Schittek 6 10 11,  Stefanie Bugl 1,  Thomas A Kufer 12,  Markus W Löffler 7 10 13,  Mathias Chamaillard 14,  Julia Skokowa 5 10,  Daniela Kramer 4,  Nathan K Archer 2,  Alexander N R Weber 15 16 17
Affiliations

Affiliations

  • 1 Institute of Immunology, Department of Innate Immunity, 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 Laboratory of Immunogenetics, Department of Immunology, Institute of Biomedical Science, University of São Paulo (USP), São Paulo, SP, Brazil.
  • 4 Department of Dermatology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
  • 5 Division of Translational Oncology, Department of Oncology, Hematology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Otfried-Müller Str. 10, 72076, Tübingen, Germany.
  • 6 Department of Dermatology, University Hospital Tübingen, Liebermeisterstr. 25, 72076, Tübingen, Germany.
  • 7 Institute of Immunology, Department of Peptide-based Immunotherapy, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany.
  • 8 Quantitative Biology Center (QBiC), University of Tübingen, Auf der Morgenstelle 10, 72076, Tübingen, Germany.
  • 9 Electron Microscopy Facility, Max Planck Institute for Biology Tübingen, Max-Planck-Ring 5, 72076, Tübingen, Germany.
  • 10 iFIT - Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany.
  • 11 CMFI - Cluster of Excellence (EXC 2124) "Controlling microbes to fight infection", University of Tübingen, Tübingen, Germany.
  • 12 Institute of Nutritional Medicine, Department of Immunology, University of Hohenheim, Fruwirthstr. 12, 70593, Stuttgart, Germany.
  • 13 Institute for Clinical and Experimental Transfusion Medicine, Medical Faculty, University of Tübingen, Otfried-Müller-Str. 4/1, 72076, Tübingen, Germany.
  • 14 University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL - Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France.
  • 15 Institute of Immunology, Department of Innate Immunity, University of Tübingen, Auf der Morgenstelle 15, 72076, Tübingen, Germany. alexander.weber@uni-tuebingen.de.
  • 16 iFIT - Cluster of Excellence (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany. alexander.weber@uni-tuebingen.de.
  • 17 CMFI - Cluster of Excellence (EXC 2124) "Controlling microbes to fight infection", University of Tübingen, Tübingen, Germany. alexander.weber@uni-tuebingen.de.
PMID: 38783164 DOI: 10.1038/s44319-024-00150-5
Abstract

Neutrophil extracellular traps (NETs) are a key antimicrobial feature of cellular innate immunity mediated by polymorphonuclear neutrophils (PMNs). NETs counteract microbes but are also linked to inflammation in atherosclerosis, arthritis, or psoriasis by unknown mechanisms. Here, we report that NET-associated RNA (naRNA) stimulates further NET formation in naive PMNs via a unique TLR8-NLRP3 inflammasome-dependent pathway. Keratinocytes respond to naRNA with expression of psoriasis-related genes (e.g., IL17, IL36) via atypical NOD2-RIPK signaling. In vivo, naRNA drives temporary skin inflammation, which is drastically ameliorated by genetic ablation of RNA sensing. Unexpectedly, the naRNA-LL37 'composite damage-associated molecular pattern (DAMP)' is pre-stored in resting neutrophil granules, defining sterile NETs as inflammatory webs that amplify neutrophil activation. However, the activity of the naRNA-LL37 DAMP is transient and hence supposedly self-limiting under physiological conditions. Collectively, upon dysregulated NET release like in psoriasis, naRNA sensing may represent both a potential cause of disease and a new intervention target.

Keywords

DAMP; NLRP3 Inflammasome; Neutrophil Extracellular Trap; RNA; Toll-like Receptors.

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