Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia
The peripheral immune system plays a critical role in neuroinflammation of the central nervous system after an insult. Hypoxic-ischemic encephalopathy (HIE) induces a strong neuroinflammatory response in neonates, which is often associated with exacerbated outcomes. In adult models of ischemic strok...
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3598 |
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| author | Maria E. Bernis Margit Zweyer Elke Maes Yvonne Schleehuber Hemmen Sabir |
| author_facet | Maria E. Bernis Margit Zweyer Elke Maes Yvonne Schleehuber Hemmen Sabir |
| author_sort | Maria E. Bernis |
| collection | DOAJ |
| description | The peripheral immune system plays a critical role in neuroinflammation of the central nervous system after an insult. Hypoxic-ischemic encephalopathy (HIE) induces a strong neuroinflammatory response in neonates, which is often associated with exacerbated outcomes. In adult models of ischemic stroke, neutrophils infiltrate injured brain tissue immediately after an ischemic insult and aggravate inflammation via various mechanisms, including neutrophil extracellular trap (NETs) formation. In this study, we used a neonatal model of experimental hypoxic-ischemic (HI) brain injury and demonstrated that circulating neutrophils were rapidly activated in neonatal blood. We observed an increased infiltration of neutrophils in the brain after exposure to HI. After treatment with either normothermia (NT) or therapeutic hypothermia (TH), we observed a significantly enhanced expression level of the NETosis marker Citrullinated H3 (Cit-H3), which was significantly more pronounced in animals treated with TH than in those treated with NT. NETs and NLR family pyrin domain containing 3 (NLRP-3) inflammasome assembly are closely linked in adult models of ischemic brain injury. In this study, we observed an increase in the activation of the NLRP-3 inflammasome at the time points analyzed, particularly immediately after TH, when we observed a significant increase in NETs structures in the brain. Together, these results suggest the important pathological functions of early arriving neutrophils and NETosis following neonatal HI, particularly after TH treatment, which is a promising starting point for the development of potential new therapeutic targets for neonatal HIE. |
| first_indexed | 2024-03-11T08:42:54Z |
| format | Article |
| id | doaj.art-5d288adc847a4835a0ea10646d3f0a85 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:42:54Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5d288adc847a4835a0ea10646d3f0a852023-11-16T21:02:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244359810.3390/ijms24043598Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic HypothermiaMaria E. Bernis0Margit Zweyer1Elke Maes2Yvonne Schleehuber3Hemmen Sabir4Department of Neonatology and Pediatric Intensive Care, Children’s Hospital, University of Bonn, 53127 Bonn, GermanyDepartment of Neonatology and Pediatric Intensive Care, Children’s Hospital, University of Bonn, 53127 Bonn, GermanyDepartment of Neonatology and Pediatric Intensive Care, Children’s Hospital, University of Bonn, 53127 Bonn, GermanyDeutsche Zentrum für Neurodegenerative Erkrankungen (DZNE), 53127 Bonn, GermanyDepartment of Neonatology and Pediatric Intensive Care, Children’s Hospital, University of Bonn, 53127 Bonn, GermanyThe peripheral immune system plays a critical role in neuroinflammation of the central nervous system after an insult. Hypoxic-ischemic encephalopathy (HIE) induces a strong neuroinflammatory response in neonates, which is often associated with exacerbated outcomes. In adult models of ischemic stroke, neutrophils infiltrate injured brain tissue immediately after an ischemic insult and aggravate inflammation via various mechanisms, including neutrophil extracellular trap (NETs) formation. In this study, we used a neonatal model of experimental hypoxic-ischemic (HI) brain injury and demonstrated that circulating neutrophils were rapidly activated in neonatal blood. We observed an increased infiltration of neutrophils in the brain after exposure to HI. After treatment with either normothermia (NT) or therapeutic hypothermia (TH), we observed a significantly enhanced expression level of the NETosis marker Citrullinated H3 (Cit-H3), which was significantly more pronounced in animals treated with TH than in those treated with NT. NETs and NLR family pyrin domain containing 3 (NLRP-3) inflammasome assembly are closely linked in adult models of ischemic brain injury. In this study, we observed an increase in the activation of the NLRP-3 inflammasome at the time points analyzed, particularly immediately after TH, when we observed a significant increase in NETs structures in the brain. Together, these results suggest the important pathological functions of early arriving neutrophils and NETosis following neonatal HI, particularly after TH treatment, which is a promising starting point for the development of potential new therapeutic targets for neonatal HIE.https://www.mdpi.com/1422-0067/24/4/3598neonatalhypoxiaischemiahypothermiainflammationNETosis |
| spellingShingle | Maria E. Bernis Margit Zweyer Elke Maes Yvonne Schleehuber Hemmen Sabir Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia International Journal of Molecular Sciences neonatal hypoxia ischemia hypothermia inflammation NETosis |
| title | Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia |
| title_full | Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia |
| title_fullStr | Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia |
| title_full_unstemmed | Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia |
| title_short | Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia |
| title_sort | neutrophil extracellular traps release following hypoxic ischemic brain injury in newborn rats treated with therapeutic hypothermia |
| topic | neonatal hypoxia ischemia hypothermia inflammation NETosis |
| url | https://www.mdpi.com/1422-0067/24/4/3598 |
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