Eosinophil ETosis and DNA Traps: a New Look at Eosinophilic Inflammation

Ueki, Shigeharu; Tokunaga, Tohru; Fujieda, Shigeharu; Honda, Kazuo; Hirokawa, Makoto; Spencer, Lisa A.; Weller, Peter F.

doi:10.1007/s11882-016-0634-5

Cited by 97 publications

(78 citation statements)

References 85 publications

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“…43,44 Upon entry into circulation, eosinophils have a short half-life before distribution into diverse tissue sites, including the lung. 43,44 Upon entry into circulation, eosinophils have a short half-life before distribution into diverse tissue sites, including the lung.…”

Section: Discussionmentioning

confidence: 99%

Variability of blood eosinophils in patients in a clinic for severe asthma

Rakowski

Zhao

Liu

et al. 2019

Clin Experimental Allergy

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Background: Blood eosinophils are used to determine eligibility for agents targeting IL-5 in patients with uncontrolled asthma. However, little is known about the variability of blood eosinophil measures in these patients before treatment initiation.Objective: To characterize variability and patterns of variability of blood eosinophil levels in a real-world clinic for severe asthmatics.Methods: Retrospective review of blood eosinophils measured over a 5-year period in patients enrolled in an urban clinic. Repeated measures of blood eosinophil levels in individuals were evaluated, and cluster analysis was performed to characterize patients by eosinophil patterns. Clinical characteristics associated with eosinophil levels and patterns of variability were analysed. Results:Patients treated in the Bellevue Hospital Asthma Clinic within a 3-month period were identified (n = 219). Blood eosinophil measures were obtained over the previous 5 years. Only 6% (n = 13) of patients had levels that were consistently above 300 cells/μL. Nearly 50% (n = 104) had eosinophil levels that traversed the threshold of 300 cells/μL. In contrast, 102 (46%) had levels that never reached the threshold of 300 cells/μL. Cluster analyses revealed three clusters with differing patterns of levels and variability. There was a suggestion of decreased clinical control and increased atopy in the cluster with the greatest variability in blood eosinophil measures. Conclusion:In an urban clinic for patients referred for uncontrolled asthma, blood measures of eosinophils were variable and showed differing patterns of variability.These data reinforce the need to perform repeated eosinophil blood measures for appropriate designation for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Variability of blood eosinophils in patients in a clinic for severe asthma

Rakowski

Zhao

Liu

et al. 2019

Clin Experimental Allergy

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“…Simultaneously, we should note that SYTOX Green‐positivity could overestimate the amount of NETs because of the presence of a small population of SYTOX Green‐positive MPO‐negative cells. Since it has been demonstrated that eosinophils can release their chromatin fibers akin to neutrophils 23, the SYTOX Green‐positive MPO‐negative population could be composed of eosinophils with extracellular chromatin fibers. Henceforth, cells which are doubly positive for SYTOX Green and MPO should be regarded as neutrophils that formed NETs.…”

Section: Discussionmentioning

confidence: 99%

Measurement of NET formation in vitro and in vivo by flow cytometry

et al. 2017

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Neutrophil extracellular traps (NETs) are extracellular chromatin fibers adorned with antimicrobial proteins, such as myeloperoxidase (MPO), which are extruded from activated neutrophils. NETosis is the metamorphosis of neutrophils with NET formation that follows decondensation of DNA and rupture of the plasma membrane. Although NETs play important roles in innate immunity, excessive formation of NETs can be harmful to the hosts. Until now, various methods for evaluation of NETs have been reported. Although each has a virtue, the gold standard has not been established. Here we demonstrate a simple, objective, and quantitative method to detect NETs using flow cytometry. This method uses a plasma membrane‐impermeable DNA‐binding dye, SYTOX Green. SYTOX Green‐positive cells were detected in human peripheral polymorphonuclear cells exposed to a NET inducer, phorbol 12‐myristate 13‐acetate (PMA). The number of SYTOX Green‐positive cells was increased depending on the exposure duration and concentrations of PMA. Furthermore, co‐localization of MPO and plasma membrane‐appendant DNA of SYTOX Green‐positive cells was demonstrated. Moreover, a NET inhibitor, diphenylene iodonium, could significantly reduce the number of SYTOX Green‐positive cells induced by PMA. The collective evidence suggests that SYTOX Green‐positive cells include neutrophils that formed NETs. The established method could detect neutrophils that underwent NETosis but not early apoptosis with equivalence in quantification to another well‐used image analysis, which is based on fluorescent staining. Additionally, NETs that were formed in vivo were also detectable by this method. It is conceivable that the established method will bring us better understanding of the relation between NETosis and human diseases. © 2017 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of ISAC.

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“…This proresolving effect is presumably caused by an IL-13-dependent shift of macrophages toward an antiinflammatory phenotype characterized by a high expression of arginase 1 and/or by the production of antiinflammatory lipids such as protectin D1 (15). Although not to the same extent as neutrophils, eosinophils also possess considerable protease activity that might exert immunoregulatory effects similar to neutrophils (22,23). However, eosinophil granules often stay intact during extracellular trap formation (22), which may possibly affect cytokine degradation.…”

Section: Role Of Eosinophils In Degradation Of Cytokines/chemokines Amentioning

confidence: 99%

Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases

et al. 2018

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Papillon-Lefèvre syndrome (PLS) is characterized by nonfunctional neutrophil serine proteases (NSPs) and fulminant periodontal inflammation of unknown cause. Here we investigated neutrophil extracellular trap (NET)-associated aggregation and cytokine/chemokine-release/degradation by normal and NSP-deficient human and mouse granulocytes. Stimulated with solid or soluble NET inducers, normal neutrophils formed aggregates and both released and degraded cytokines/chemokines. With increasing cell density, proteolytic degradation outweighed release. Maximum output of cytokines/chemokines occurred mostly at densities between 2 × 10 and 4 × 10 neutrophils/cm. Assessment of neutrophil density in vivo showed that these concentrations are surpassed during inflammation. Association with aggregated NETs conferred protection of neutrophil elastase against α1-antitrypsin. In contrast, eosinophils did not influence cytokine/chemokine concentrations. The proteolytic degradation of inflammatory mediators seen in NETs was abrogated in Papillon-Lefèvre syndrome (PLS) neutrophils. In summary, neutrophil-driven proteolysis of inflammatory mediators works as a built-in safeguard for inflammation. The absence of this negative feedback mechanism might be responsible for the nonresolving periodontitis seen in PLS.-Hahn, J., Schauer, C., Czegley, C., Kling, L., Petru, L., Schmid, B., Weidner, D., Reinwald, C., Biermann, M. H. C., Blunder, S., Ernst, J., Lesner, A., Bäuerle, T., Palmisano, R., Christiansen, S., Herrmann, M., Bozec, A., Gruber, R., Schett, G., Hoffmann, M. H. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases.

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Eosinophil ETosis and DNA Traps: a New Look at Eosinophilic Inflammation

Cited by 97 publications

References 85 publications

Variability of blood eosinophils in patients in a clinic for severe asthma

Variability of blood eosinophils in patients in a clinic for severe asthma

Measurement of NET formation in vitro and in vivo by flow cytometry

Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases

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