Neutrophils Express Distinct RNA Receptors in a Non-canonical Way

Berger, Michael; Hsieh, Chin Yuan; Bakele, Martina; Marcos, Verónica; Rieber, Nikolaus; Kormann, Michael; Mays, Lauren; Hofer, Laura; Neth, Olaf; Vitkov, Ljubomir; Krautgartner, Wolf‐Dietrich; Schweinitz, Dietrich von; Kappler, Roland; Hector, Andreas; Weber, Alexander N.R.; Hartl, Dominik

doi:10.1074/jbc.m112.353557

Cited by 49 publications

(55 citation statements)

References 22 publications

(40 reference statements)

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“…This method has been established and described previously by us (23) and has been adapted in a modified form from the method described previously in detail by Clemmensen et al (24,25). In brief, neutrophils isolated from peripheral blood were resuspended in disruption buffer (100 mM KCl, 3 mM NaCl, 1 mM Na 2 ATP, 3.5 mM MgCl 2 , 10 mM PIPES, pH 7.2) with a protease inhibitor mixture added as described by the manufacturer (Roche Applied Science).…”

Section: Methodsmentioning

confidence: 99%

Localization and Functionality of the Inflammasome in Neutrophils

Bakele

Joos

Burdi

et al. 2014

Journal of Biological Chemistry

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135

137

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Background:The inflammasome generates IL-1 family proteins, but its role in neutrophils is poorly understood. Results: Neutrophils store key inflammasome components in distinct intracellular compartments and release IL-1␤ and IL-18, but not IL-1␣ or IL-33. Conclusion: Neutrophils store inflammasome components in intracellular compartments. Significance: Targeting the inflammasome in neutrophils represents a future anti-inflammatory strategy.

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Section: Methodsmentioning

confidence: 99%

Localization and Functionality of the Inflammasome in Neutrophils

Bakele

Joos

Burdi

et al. 2014

Journal of Biological Chemistry

Self Cite

135

137

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“…Neutrophil Isolation-Human neutrophils were isolated as described previously by us (10). In brief, peripheral blood was obtained from healthy volunteers in accordance with the institutional review board and approved by the Ethical Committees of the Ludwig Maximilians University Munich and the University of Tübingen.…”

Section: Methodsmentioning

confidence: 99%

“…Subcellular Fractionation of Neutrophils-Subcellular fractionation of neutrophils was performed by nitrogen cavitation and sedimentation of the postnuclear supernatant on a fourlayer Percoll density gradients, as described previously in detail by Clemmensen et al (11,12) and our studies (10,13). In brief, neutrophils isolated from peripheral blood were resuspended in disruption buffer (100 mM KCl, 3 mM NaCl, 1 mM Na 2 ATP 3.5 mM MgCl 2 , 10 mM PIPES, pH 7.2) with a protease inhibitor mixture added as described by the manufacturer (11836153001, Roche Applied Science).…”

Section: Methodsmentioning

confidence: 99%

An Interactive Network of Elastase, Secretases, and PAR-2 Protein Regulates CXCR1 Receptor Surface Expression on Neutrophils

Bakele

Lotz-Havla

Jakowetz

et al. 2014

Journal of Biological Chemistry

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Background: IL-8 activates neutrophils through CXCR1. Elastase cleaves CXCR1, but the cellular machinery involved remains poorly understood. Results: Here we show that secretases and PAR-2 regulate elastase-mediated cleavage of CXCR1. Conclusion: These studies establish a novel network of elastase, secretases, and PAR-2 that regulates CXCR1 on neutrophils. Significance: Targeting this network may lead to novel therapeutic strategies in neutrophilic diseases, such as cystic fibrosis.

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“…1F, G) and bright-field fluorescence microscopy with Atto488-labeled LL37 showed co-localization of Alexa647-RNA and Atto488-LL37 in intracellular compartments (Fig. 1H) where TLR8 is expressed 18 .…”

Section: Ll37 Promotes Rna Uptake and Induces Tlr8-mediated Pmn Activmentioning

confidence: 94%

“…Additionally, PMNs are able to undergo neutrophil extracellular trap (NET) formation (NETosis), an activation-induced process leading to the extrusion of nuclear DNA 16 , as well as cellular proteins, including LL37 17 . Like pDCs, PMNs express multiple pattern recognition receptors (PRRs) of the Toll-like receptor (TLR) family, namely TLR2, 4, 8 18 and 9…”

Section: Introductionmentioning

confidence: 99%

RNA-antimicrobial peptide LL-37 complexes fuel a TLR- and NET-mediated inflammatory cycle of neutrophil activation in psoriasis

Herster

Bittner

Dickhoefer

et al. 2018

Preprint

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KeywordsLL37, RNA, Psoriasis, Neutrophil, Toll-like receptor (TLR) Key pointsHuman neutrophils respond to host and foreign RNA when complexed to the psoriasis-associated antimicrobial peptide, LL37The resulting release of cytokines requires TLRs, is elevated in psoriasis patients and can be blocked using inhibitor oligodeoxynucleotides AbstractPsoriasis is an inflammatory autoimmune disease characterized by skin lesions showing strong immune cells infiltration and high levels of the antimicrobial peptide, LL37. LL37 binds RNA and DNA and these complexes trigger Toll-like receptors (TLRs) and subsequent interferon release from plasmacytoid dendritic cells. Polymorphonuclear leukocytes (PMNs) are abundant in psoriatic skin and are primary sources for LL37, extracellular nucleic acids and inflammatory cytokines. We hypothesized that LL37-nucleic acid complexes sustain a self-amplifying inflammatory loop via TLR signaling in PMNs but this hypothesis has not been investigated. We here show that LL37 potentiated TLR8-mediated IL-8 release by PMNs in response to synthetic, human and bacterial RNA, by promoting its uptake. Additionally, RNA complexed to LL37 prompted PMNs to produce TNF, IL-6 and IL-1β, as well as the chemoattractants IL-16 and MIP-1β. Interestingly, in PMNs from psoriasis patients, TLR-triggered cytokine and chemokine release and constitutive LL37 secretion were generally elevated compared to PMNs from healthy donors and RNA triggered IL-8 even in the absence of exogenous LL37. Finally, we observed that inhibitory oligodeoxynucleotides (iODNs), previously used to block TLR7 and TLR9 responses, prevented the TLR response of PMNs to RNA-LL37 complexes. Collectively, our data suggest that in psoriatic lesions RNA-LL37-driven PMN activation may contribute to a vicious cycle of inflammation and immune cells attraction, and that TLR blockade could be used to limit PMN-mediated inflammation and immune cell infiltration in this context.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Neutrophils Express Distinct RNA Receptors in a Non-canonical Way

Cited by 49 publications

References 22 publications

Localization and Functionality of the Inflammasome in Neutrophils

Localization and Functionality of the Inflammasome in Neutrophils

An Interactive Network of Elastase, Secretases, and PAR-2 Protein Regulates CXCR1 Receptor Surface Expression on Neutrophils

RNA-antimicrobial peptide LL-37 complexes fuel a TLR- and NET-mediated inflammatory cycle of neutrophil activation in psoriasis

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