Kristof Van Avondt, Marein Schimmel, Ingrid Bulder, Gerard van Mierlo, Erfan Nur, Robin van Bruggen, Bart J Biemond, Brenda M Luken, Sacha Zeerleder
{"title":"镰状细胞病患者的循环铁介导中性粒细胞外陷阱的释放。","authors":"Kristof Van Avondt, Marein Schimmel, Ingrid Bulder, Gerard van Mierlo, Erfan Nur, Robin van Bruggen, Bart J Biemond, Brenda M Luken, Sacha Zeerleder","doi":"10.1159/000526760","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Neutrophils promote chronic inflammation and release neutrophil extracellular traps (NETs) that can drive inflammatory responses. Inflammation influences progression of sickle cell disease (SCD), and a role for NETs has been suggested in the onset of vaso-occlusive crisis (VOC). We aimed to identify factors in the circulation of these patients that provoke NET release, with a focus on triggers associated with hemolysis.</p><p><strong>Methods: </strong>Paired serum and plasma samples during VOC and steady state of 18 SCD patients (HbSS/HbSβ<sup>0</sup>-thal and HbSC/HbSβ<sup>+</sup>-thal) were collected. Cell-free heme, hemopexin, and labile plasma iron have been measured in the plasma samples of the SCD patients. NETs formation by human neutrophils from healthy donors induced by serum of SCD patients was studied using confocal microscopy and staining for extracellular DNA using Sytox, followed by quantification of surface coverage using ImageJ.</p><p><strong>Results: </strong>Eighteen patients paired samples obtained during VOC and steady state were available (11 HbSS/HbSβ<sup>0</sup>-thal and 7 HbSC/HbSβ<sup>+</sup>-thal). We observed high levels of systemic heme and iron, concomitant with low levels of the heme-scavenger hemopexin in sera of patients with SCD, both during VOC and in steady state. In our in vitro experiments, neutrophils released NETs when exposed to sera from SCD patients. The release of NETs was associated with high levels of circulating iron in these sera. Although hemin triggered NET formation in vitro, addition of hemopexin to scavenge heme did not suppress NET release in SCD sera. By contrast, the iron scavengers deferoxamine and apotransferrin attenuated NET formation in a significant proportion of SCD sera.</p><p><strong>Discussion: </strong>Our results suggest that redox-active iron in the circulation of non-transfusion-dependent SCD patients activates neutrophils to release NETs, and hence, exerts a direct pro-inflammatory effect. Thus, we propose that chelation of iron requires further investigation as a therapeutic strategy in SCD.</p>","PeriodicalId":23252,"journal":{"name":"Transfusion Medicine and Hemotherapy","volume":"50 4","pages":"321-329"},"PeriodicalIF":1.9000,"publicationDate":"2023-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/96/b0/tmh-0050-0321.PMC10521246.pdf","citationCount":"0","resultStr":"{\"title\":\"Circulating Iron in Patients with Sickle Cell Disease Mediates the Release of Neutrophil Extracellular Traps.\",\"authors\":\"Kristof Van Avondt, Marein Schimmel, Ingrid Bulder, Gerard van Mierlo, Erfan Nur, Robin van Bruggen, Bart J Biemond, Brenda M Luken, Sacha Zeerleder\",\"doi\":\"10.1159/000526760\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Neutrophils promote chronic inflammation and release neutrophil extracellular traps (NETs) that can drive inflammatory responses. Inflammation influences progression of sickle cell disease (SCD), and a role for NETs has been suggested in the onset of vaso-occlusive crisis (VOC). We aimed to identify factors in the circulation of these patients that provoke NET release, with a focus on triggers associated with hemolysis.</p><p><strong>Methods: </strong>Paired serum and plasma samples during VOC and steady state of 18 SCD patients (HbSS/HbSβ<sup>0</sup>-thal and HbSC/HbSβ<sup>+</sup>-thal) were collected. Cell-free heme, hemopexin, and labile plasma iron have been measured in the plasma samples of the SCD patients. NETs formation by human neutrophils from healthy donors induced by serum of SCD patients was studied using confocal microscopy and staining for extracellular DNA using Sytox, followed by quantification of surface coverage using ImageJ.</p><p><strong>Results: </strong>Eighteen patients paired samples obtained during VOC and steady state were available (11 HbSS/HbSβ<sup>0</sup>-thal and 7 HbSC/HbSβ<sup>+</sup>-thal). We observed high levels of systemic heme and iron, concomitant with low levels of the heme-scavenger hemopexin in sera of patients with SCD, both during VOC and in steady state. In our in vitro experiments, neutrophils released NETs when exposed to sera from SCD patients. The release of NETs was associated with high levels of circulating iron in these sera. Although hemin triggered NET formation in vitro, addition of hemopexin to scavenge heme did not suppress NET release in SCD sera. By contrast, the iron scavengers deferoxamine and apotransferrin attenuated NET formation in a significant proportion of SCD sera.</p><p><strong>Discussion: </strong>Our results suggest that redox-active iron in the circulation of non-transfusion-dependent SCD patients activates neutrophils to release NETs, and hence, exerts a direct pro-inflammatory effect. 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Circulating Iron in Patients with Sickle Cell Disease Mediates the Release of Neutrophil Extracellular Traps.
Introduction: Neutrophils promote chronic inflammation and release neutrophil extracellular traps (NETs) that can drive inflammatory responses. Inflammation influences progression of sickle cell disease (SCD), and a role for NETs has been suggested in the onset of vaso-occlusive crisis (VOC). We aimed to identify factors in the circulation of these patients that provoke NET release, with a focus on triggers associated with hemolysis.
Methods: Paired serum and plasma samples during VOC and steady state of 18 SCD patients (HbSS/HbSβ0-thal and HbSC/HbSβ+-thal) were collected. Cell-free heme, hemopexin, and labile plasma iron have been measured in the plasma samples of the SCD patients. NETs formation by human neutrophils from healthy donors induced by serum of SCD patients was studied using confocal microscopy and staining for extracellular DNA using Sytox, followed by quantification of surface coverage using ImageJ.
Results: Eighteen patients paired samples obtained during VOC and steady state were available (11 HbSS/HbSβ0-thal and 7 HbSC/HbSβ+-thal). We observed high levels of systemic heme and iron, concomitant with low levels of the heme-scavenger hemopexin in sera of patients with SCD, both during VOC and in steady state. In our in vitro experiments, neutrophils released NETs when exposed to sera from SCD patients. The release of NETs was associated with high levels of circulating iron in these sera. Although hemin triggered NET formation in vitro, addition of hemopexin to scavenge heme did not suppress NET release in SCD sera. By contrast, the iron scavengers deferoxamine and apotransferrin attenuated NET formation in a significant proportion of SCD sera.
Discussion: Our results suggest that redox-active iron in the circulation of non-transfusion-dependent SCD patients activates neutrophils to release NETs, and hence, exerts a direct pro-inflammatory effect. Thus, we propose that chelation of iron requires further investigation as a therapeutic strategy in SCD.
期刊介绍：
This journal is devoted to all areas of transfusion medicine. These include the quality and security of blood products, therapy with blood components and plasma derivatives, transfusion-related questions in transplantation, stem cell manipulation, therapeutic and diagnostic problems of homeostasis, immuno-hematological investigations, and legal aspects of the production of blood products as well as hemotherapy. Both comprehensive reviews and primary publications that detail the newest work in transfusion medicine and hemotherapy promote the international exchange of knowledge within these disciplines. Consistent with this goal, continuing clinical education is also specifically addressed.
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