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Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia

Neonatal encephalopathy (NE) is a significant cause of morbidity and mortality. Persistent inflammation and activation of leukocytes mediate brain injury in NE. The standard of care for NE, therapeutic hypothermia (TH), does not improve outcomes in nearly half of moderate to severe cases, resulting...

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Autores principales: O'Dea, Mary Isabel, Kelly, Lynne, McKenna, Ellen, Melo, Ashanty M., Ni Bhroin, Megan, Hurley, Tim, Byrne, Angela T., Colleran, Gabrielle, Vavasseur, Claudine, El-Khuffash, Afif, Miletin, Jan, Murphy, John, Hickey, Fionnuala, Molloy, Eleanor J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917189/
https://www.ncbi.nlm.nih.gov/pubmed/33659224
http://dx.doi.org/10.3389/fped.2020.598724
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author O'Dea, Mary Isabel
Kelly, Lynne
McKenna, Ellen
Melo, Ashanty M.
Ni Bhroin, Megan
Hurley, Tim
Byrne, Angela T.
Colleran, Gabrielle
Vavasseur, Claudine
El-Khuffash, Afif
Miletin, Jan
Murphy, John
Hickey, Fionnuala
Molloy, Eleanor J.
author_facet O'Dea, Mary Isabel
Kelly, Lynne
McKenna, Ellen
Melo, Ashanty M.
Ni Bhroin, Megan
Hurley, Tim
Byrne, Angela T.
Colleran, Gabrielle
Vavasseur, Claudine
El-Khuffash, Afif
Miletin, Jan
Murphy, John
Hickey, Fionnuala
Molloy, Eleanor J.
author_sort O'Dea, Mary Isabel
collection PubMed
description Neonatal encephalopathy (NE) is a significant cause of morbidity and mortality. Persistent inflammation and activation of leukocytes mediate brain injury in NE. The standard of care for NE, therapeutic hypothermia (TH), does not improve outcomes in nearly half of moderate to severe cases, resulting in the need for new adjuvant therapies, and immunomodulation holds promise. Our objective was to explore systemic leukocyte phenotype in infants with NE and healthy controls in response to lipopolysaccharide (LPS). Twenty-four infants with NE (NE II-20; NE III = 4) requiring TH and 17 term neonatal controls were enrolled, and blood samples were analyzed between days 1 and 4 of life at a mean (SD) timepoint of 2.1 (± 0.81) days of postnatal life at the time of the routine phlebotomy. Leukocyte cell surface expression levels of Toll-like receptor 4, NADPH oxidase (NOX2), CD11b, mitochondrial mass, and mitochondrial superoxide production were measured by flow cytometry. Gene expression of TRIF (TIR domain–containing adapter-inducing interferon-β), MyD88 and IRAK4 was measured by reverse transcription–polymerase chain reaction. Infants with NE had significantly lower expression of neutrophil CD11b and NOX2 with LPS stimulation compared to healthy term controls. Mitochondrial mass in neutrophils and monocytes was significantly increased in NE infants with LPS compared to controls, potentially indicating a dysregulated metabolism. Infants with NE had significantly lower IRAK4 at baseline than controls. NE infants display a dysregulated inflammatory response compared to healthy infants, with LPS hyporesponsiveness to CD11b and NOX2 and decreased IRAK4 gene expression. This dysregulated immune profile may indicate an adaptable response to limit hyperinflammation.
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spelling pubmed-79171892021-03-02 Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia O'Dea, Mary Isabel Kelly, Lynne McKenna, Ellen Melo, Ashanty M. Ni Bhroin, Megan Hurley, Tim Byrne, Angela T. Colleran, Gabrielle Vavasseur, Claudine El-Khuffash, Afif Miletin, Jan Murphy, John Hickey, Fionnuala Molloy, Eleanor J. Front Pediatr Pediatrics Neonatal encephalopathy (NE) is a significant cause of morbidity and mortality. Persistent inflammation and activation of leukocytes mediate brain injury in NE. The standard of care for NE, therapeutic hypothermia (TH), does not improve outcomes in nearly half of moderate to severe cases, resulting in the need for new adjuvant therapies, and immunomodulation holds promise. Our objective was to explore systemic leukocyte phenotype in infants with NE and healthy controls in response to lipopolysaccharide (LPS). Twenty-four infants with NE (NE II-20; NE III = 4) requiring TH and 17 term neonatal controls were enrolled, and blood samples were analyzed between days 1 and 4 of life at a mean (SD) timepoint of 2.1 (± 0.81) days of postnatal life at the time of the routine phlebotomy. Leukocyte cell surface expression levels of Toll-like receptor 4, NADPH oxidase (NOX2), CD11b, mitochondrial mass, and mitochondrial superoxide production were measured by flow cytometry. Gene expression of TRIF (TIR domain–containing adapter-inducing interferon-β), MyD88 and IRAK4 was measured by reverse transcription–polymerase chain reaction. Infants with NE had significantly lower expression of neutrophil CD11b and NOX2 with LPS stimulation compared to healthy term controls. Mitochondrial mass in neutrophils and monocytes was significantly increased in NE infants with LPS compared to controls, potentially indicating a dysregulated metabolism. Infants with NE had significantly lower IRAK4 at baseline than controls. NE infants display a dysregulated inflammatory response compared to healthy infants, with LPS hyporesponsiveness to CD11b and NOX2 and decreased IRAK4 gene expression. This dysregulated immune profile may indicate an adaptable response to limit hyperinflammation. Frontiers Media S.A. 2021-02-15 /pmc/articles/PMC7917189/ /pubmed/33659224 http://dx.doi.org/10.3389/fped.2020.598724 Text en Copyright © 2021 O'Dea, Kelly, McKenna, Melo, Ni Bhroin, Hurley, Byrne, Colleran, Vavasseur, El-Khuffash, Miletin, Murphy, Hickey and Molloy. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pediatrics
O'Dea, Mary Isabel
Kelly, Lynne
McKenna, Ellen
Melo, Ashanty M.
Ni Bhroin, Megan
Hurley, Tim
Byrne, Angela T.
Colleran, Gabrielle
Vavasseur, Claudine
El-Khuffash, Afif
Miletin, Jan
Murphy, John
Hickey, Fionnuala
Molloy, Eleanor J.
Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia
title Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia
title_full Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia
title_fullStr Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia
title_full_unstemmed Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia
title_short Dysregulated Monocyte and Neutrophil Functional Phenotype in Infants With Neonatal Encephalopathy Requiring Therapeutic Hypothermia
title_sort dysregulated monocyte and neutrophil functional phenotype in infants with neonatal encephalopathy requiring therapeutic hypothermia
topic Pediatrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917189/
https://www.ncbi.nlm.nih.gov/pubmed/33659224
http://dx.doi.org/10.3389/fped.2020.598724
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