naRNA-LL37 composite DAMPs define sterile NETs as self-propagating drivers of inflammation
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Published:2024-05-23
Issue:7
Volume:25
Page:2914-2949
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ISSN:1469-3178
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Container-title:EMBO Reports
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language:en
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Short-container-title:EMBO Rep
Author:
Bork FrancescaORCID, Greve Carsten L, Youn Christine, Chen Sirui, N C Leal Vinicius, Wang Yu, Fischer BereniceORCID, Nasri Masoud, Focken Jule, Scheurer Jasmin, Engels PujanORCID, Dubbelaar MarissaORCID, Hipp KatharinaORCID, Zalat BaherORCID, Szolek Andras, Wu Meng-Jen, Schittek BirgitORCID, Bugl Stefanie, Kufer Thomas AORCID, Löffler Markus WORCID, Chamaillard MathiasORCID, Skokowa JuliaORCID, Kramer Daniela, Archer Nathan KORCID, Weber Alexander N RORCID
Abstract
AbstractNeutrophil 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.
Funder
Deutsche Forschungsgemeinschaft HHS | National Institutes of Health Pfizer Boehringer Ingelheim Sao Paolo Research Foundation Volkswagen Foundation Eberhard Karls Universität Tübingen University of Tübingen | Medizinischen Fakultät, Eberhard Karls Universität Tübingen
Publisher
Springer Science and Business Media LLC
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