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; Alexander N.R. Weber

doi:10.1038/s41467-019-13756-4

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, Alexander N.R. Weber

School of Medicine

Research output: Contribution to journal › Article

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.

Original language	English (US)
Article number	105
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13756-4
State	Published - Dec 1 2020

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ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

Cite this

Herster, F., Bittner, Z., Archer, N. K., Dickhöfer, S., Eisel, D., Eigenbrod, T., Knorpp, T., Schneiderhan-Marra, N., Löffler, M. W., Kalbacher, H., Vierbuchen, T., Heine, H., Miller, L. S., Hartl, D., Freund, L., Schäkel, K., Heister, M., Ghoreschi, K., & Weber, A. N. R. (2020). Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis. Nature communications, 11(1), [105]. https://doi.org/10.1038/s41467-019-13756-4

Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis. / Herster, Franziska; Bittner, Zsofia; Archer, Nathan K.; Dickhöfer, Sabine; Eisel, David; Eigenbrod, Tatjana; Knorpp, Thomas; Schneiderhan-Marra, Nicole; Löffler, Markus W.; Kalbacher, Hubert; Vierbuchen, Tim; Heine, Holger; Miller, Lloyd S.; Hartl, Dominik; Freund, Lukas; Schäkel, Knut; Heister, Martin; Ghoreschi, Kamran; Weber, Alexander N.R.

In: Nature communications, Vol. 11, No. 1, 105, 01.12.2020.

Research output: Contribution to journal › Article

Herster, F, Bittner, Z, Archer, NK, Dickhöfer, S, Eisel, D, Eigenbrod, T, Knorpp, T, Schneiderhan-Marra, N, Löffler, MW, Kalbacher, H, Vierbuchen, T, Heine, H, Miller, LS, Hartl, D, Freund, L, Schäkel, K, Heister, M, Ghoreschi, K & Weber, ANR 2020, 'Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis', Nature communications, vol. 11, no. 1, 105. https://doi.org/10.1038/s41467-019-13756-4

Herster, Franziska ; Bittner, Zsofia ; Archer, Nathan K. ; Dickhöfer, Sabine ; Eisel, David ; Eigenbrod, Tatjana ; Knorpp, Thomas ; Schneiderhan-Marra, Nicole ; Löffler, Markus W. ; Kalbacher, Hubert ; Vierbuchen, Tim ; Heine, Holger ; Miller, Lloyd S. ; Hartl, Dominik ; Freund, Lukas ; Schäkel, Knut ; Heister, Martin ; Ghoreschi, Kamran ; Weber, Alexander N.R. / Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis. In: Nature communications. 2020 ; Vol. 11, No. 1.

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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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AU - Freund, Lukas

AU - Schäkel, Knut

AU - Heister, Martin

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AU - Weber, Alexander N.R.

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10.1038/s41467-019-13756-4