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

Frontiers in Pediatrics

Angela T. Byrne¹  Tim Hurley²  Jan Miletin³  Mary Isabel O'Dea⁴  Eleanor J. Molloy⁵  Gabrielle Colleran⁶  Claudine Vavasseur⁷  John Murphy⁷  Afif El-Khuffash⁸  Megan Ni Bhroin⁹  Fionnuala Hickey^1,10  Lynne Kelly^1,11  Ellen McKenna^1,11  Ashanty M. Melo^1,11 

[1] Children's Health Ireland at Crumlin, Dublin, Ireland;Department of Paediatrics and Child Health, Trinity College Dublin, Dublin, Ireland;Department of Paediatrics and Neonatology, Coombe Women & Infants University Hospital, Dublin, Ireland;Department of Paediatrics and Neonatology, Coombe Women & Infants University Hospital, Dublin, Ireland;Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland;National Children's Research Centre (NCRC), Crumlin, Ireland;Department of Paediatrics and Neonatology, Coombe Women & Infants University Hospital, Dublin, Ireland;Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland;National Children's Research Centre (NCRC), Crumlin, Ireland;Our Lady's Children's Hospital (CHI), Crumlin, Ireland;Department of Paediatrics, Tallaght University Hospital, Dublin, Ireland;Department of Radiology, National Maternity Hospital, Dublin, Ireland;National Maternity Hospital, Dublin, Ireland;Rotunda Hospital, Dublin, Ireland;Trinity College Institute of Neuroscience and Cognitive Systems Group, Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland;Trinity Health Kidney Centre, Faculty of Health Sciences, School of Medicine, Trinity College Dublin, Dublin, Ireland;Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland;

关键词: neuroimmunology;    monocytes;    neutrophils;    neonatal encephalopathy;    innate immunity;   

DOI  :  10.3389/fped.2020.598724

来源: Frontiers

【 摘 要 】

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.

【 授权许可】

CC BY