Flavonoids and 5-Aminosalicylic Acid Inhibit the Formation of Neutrophil Extracellular Traps

Kirchner, Tina; Hermann, Eva; Möller, Sonja; Klinger, Matthias; Solbach, Werner; Laskay, Tamás; Behnen, Martina

doi:10.1155/2013/710239

Cited by 71 publications

(64 citation statements)

References 81 publications

(132 reference statements)

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“…Treatment of neutrophils with the NADPH oxidase inhibitor DPI, the glutathione peroxidase precursor substrate NAC, and the HOCl scavenger taurine abrogated total ROS release, a finding that is in accordance with data previously reported (44)(45)(46). NET release was inhibited only marginally in response to the bacterial challenge.…”

Section: Figsupporting

confidence: 91%

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

et al. 2017

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Oral bacteria are the main trigger for the development of periodontitis, and some species are known to modulate neutrophil function. This study aimed to explore the release of neutrophil extracellular traps (NETs), associated antimicrobial proteins, and reactive oxygen species (ROS) in response to periodontal bacteria, as well as the underlying pathways. Isolated peripheral blood neutrophils were stimulated with 19 periodontal bacteria. NET and ROS release, as well as the expression of NET-bound antimicrobial proteins, elastase, myeloperoxidase, and cathepsin G, in response to these species was measured using fluorescence-based assays. NET and ROS release was monitored after the addition of NADP (NADPH) oxidase pathway modulators and inhibitors of Toll-like receptors (TLRs). Moreover, bacterial entrapment by NETs was visualized microscopically, and bacterial killing was assessed by bacterial culture. Certain microorganisms, e.g., Veillonella parvula and Streptococcus gordonii, stimulated higher levels of ROS and NET release than others. NETs were found to entrap, but not kill, all periodontal bacteria tested. NADPH oxidase pathway modulators decreased ROS production but not NET production in response to the bacteria. Interestingly, TLR inhibitors did not impact ROS and NET release. These data suggest that the variability in the neutrophil response toward different bacteria may contribute to the pathogenesis of periodontal diseases by mechanisms such as bacterial avoidance of host responses and activation of neutrophils. Moreover, our results indicate that bacterium-stimulated NET release may arise in part via NADPH oxidase-independent mechanisms. The role of TLR signaling in bacterium-induced ROS and NET release needs to be further elucidated.KEYWORDS neutrophils, NETs, reactive oxygen species, periodontitis, oral bacteria P eriodontitis is initiated by the accumulation of microbial biofilms at and below the gingival margin. Indeed, it has been estimated that ϳ700 oral bacterial species and ϳ1,200 predominant phylotypes exist (1-3). Of these bacterial species, 5 major bacterial complexes (red, orange, yellow, green, and purple) have been identified by Socransky et al. using DNA probes (4) and are referred to here as Socransky complexes. The clustering and ordination analysis allowed them to assign microbial species to a color complex on the basis of the strength of the association with each other and the clinical staging of periodontitis. The biofilms which develop during disease are orchestrated to maximize their adherence, communication, and survival. The accumulation of bacterial species within the biofilm enables its development and perseverance, and certain bacteria, such as Fusobacterium nucleatum, are key orchestrators of biofilm formation and maturation (5).In susceptible individuals, dysbiosis and an aberrant host-microbe equilibrium can result in the onset of disease (6), where the microbial biofilm thrives by exploiting the

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Section: Figsupporting

confidence: 91%

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

et al. 2017

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“…Because iIC-induced NETosis depends on ROS, any molecule that inhibits generation of ROS or scavenges ROS could be a possible therapeutic agent. We could show that inhibitors of NOX and MPO as well as antioxidants, such as 5-ASA and vitamin C, which act as scavengers against superoxide, hydroxyl radicals, and hypochlorite (48,52), are able to reduce iIC-induced ROS and NETosis. Thus, these substances may mediate a therapeutic effect in autoimmune diseases.…”

Section: Discussionmentioning

confidence: 98%

“…The lucigenin-amplified chemiluminescence assay (46,48) was performed the same way as the luminol assay, but with 0.2 mM lucigenin (Alexis, Lörrach, Germany) instead of luminol. This assay was used to analyze the extracellular superoxide production.…”

Section: Detection Of Extracellular Superoxidementioning

confidence: 99%

“…For FM, 10 6 neutrophils/ml in NET medium were incubated for 7 h at 37˚C in iIC-coated ibiTreat m-slides (Ibidi). Following fixation with 4% paraformaldehyde (Sigma-Aldrich), staining of MPO and DNA by using mouse anti-human MPO (1:500, AbD Serotec, D€ usseldorf, Germany) and Sytox Green was carried out as described previously (4,48). Samples were analyzed with the AxioVert A.1 using the the AxioCam HRc and AxioVision release 4.8 software (all Carl Zeiss, Jena, Germany) or with the Keyence BZ-9000E using the BZ II analyzer software (Keyence, NeuIsenburg, Germany).…”

Section: Microscopical Assessment Of Netsmentioning

confidence: 99%

“…Following incubation for 7 h at 37˚C, the supernatant was removed and samples were fixed with 1 ml Monti-Graziadei solution and processed for EM as described (48). Preparates were examined with an EM505 (Philips, Eindhoven, The Netherlands).…”

Section: Microscopical Assessment Of Netsmentioning

confidence: 99%

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Immobilized Immune Complexes Induce Neutrophil Extracellular Trap Release by Human Neutrophil Granulocytes via FcγRIIIB and Mac-1

Behnen

Leschczyk

Möller

et al. 2014

The Journal of Immunology

Self Cite

217

191

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Canonical neutrophil antimicrobial effector mechanisms, such as degranulation, production of reactive oxygen species, and release of neutrophil extracellular traps (NETs), can result in severe pathology. Activation of neutrophils through immune complexes (ICs) plays a central role in the pathogenesis of many autoimmune inflammatory diseases. In this study, we report that immobilized ICs (iICs), which are hallmarks of several autoimmune diseases, induce the release of NETs from primary human neutrophils. The iIC-induced NET formation was found to require production of reactive oxygen species by NADPH oxidase and myeloperoxidase and to be mediated by FcγRIIIb. Blocking of the β2 integrin macrophage-1 Ag but not lymphocyte function–associated Ag-1 abolished iIC-induced NET formation. This suggests that FcγRIIIb signals in association with macrophage-1 Ag. As intracellular signaling pathways involved in iIC-induced NET formation we identified the tyrosine kinase Src/Syk pathway, which downstream regulates the PI3K/Akt, p38 MAPK, and ERK1/2 pathways. To our knowledge, the present study shows for the first time that iICs induce NET formation. Thus, we conclude that NETs contribute to pathology in autoimmune inflammatory disorders associated with surface-bound ICs.

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Neutrophil extracellular traps: Potential targets for the treatment of rheumatoid arthritis with traditional Chinese medicine and natural products

Liu,

Qu,

Liu

et al. 2024

Phytotherapy Research

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Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease. Abnormal formation of neutrophil extracellular traps (NETs) at the synovial membrane leads to the release of many inflammatory cytokines, including IL‐1β, IL‐6, and TNF‐α. Elastase, histone H3, and myeloperoxidase, which are carried by NETs, damage the soft tissues of the joints and aggravate the progression of RA. The balance of NET formation coordinates the pro‐inflammatory and anti‐inflammatory effects and plays a key role in the development of RA. Therefore, when NETs are used as effector targets, highly targeted drugs with fewer side effects can be developed to treat RA without damaging the host immune system. Currently, an increasing number of studies have shown that traditional Chinese medicines and natural products can regulate the formation of NETs through multiple pathways to counteract RA, which shows great potential for the treatment of RA and has a promising future for clinical application. In this article, we review the latest biological progress in understanding NET formation, the mechanism of NETs in RA, and the potential targets or pathways related to the modulation of NET formation by Chinese medicines and natural products. This review provides a relevant basis for the use of Chinese medicines and natural products as natural adjuvants in the treatment of RA.

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Flavonoids and 5-Aminosalicylic Acid Inhibit the Formation of Neutrophil Extracellular Traps

Cited by 71 publications

References 81 publications

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

Modulation of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by Periodontal Bacteria

Immobilized Immune Complexes Induce Neutrophil Extracellular Trap Release by Human Neutrophil Granulocytes via FcγRIIIB and Mac-1

Neutrophil extracellular traps: Potential targets for the treatment of rheumatoid arthritis with traditional Chinese medicine and natural products

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