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

O’Dea, Mary; Kelly, Lynne; McKenna, Ellen; Melo, Ashanty M; Bhroin, Megan Ní; Hurley, Tim; Byrne, Angela T.; Colleran, Gabrielle; Vavasseur, Claudine; El-Khuffash, Afif; Miletin, Jan; Murphy, John F.; Hickey, Fionnuala B.; Molloy, Eleanor J.

doi:10.3389/fped.2020.598724

Cited by 5 publications

(5 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Munoz et al demonstrated a reduced LPSinduced production of cytokines of IL-1α, IL-1β, IL-6, and TNF-α production in adult patients with sepsis, which was exacerbated in non-survivors (29). We demonstrated a hypo-responsiveness to LPS in NE infants with lower leucocyte activation markers of CD11b and NOX2 as compared with healthy term neonatal controls (17).…”

Section: Discussionsupporting

confidence: 49%

See 1 more Smart Citation

Altered Cytokine Endotoxin Responses in Neonatal Encephalopathy Predict MRI Outcomes

et al. 2021

Self Cite

View full text Add to dashboard Cite

Background: Neonatal encephalopathy (NE) is associated with adverse neurodevelopmental outcome and is linked with systemic inflammation. Pro-inflammatory and anti-inflammatory cytokines are known to play a role in the pathology of NE by activating innate immune cells.Methods: Eighty-seven infants were enrolled including 53 infants with NE of whom 52 received therapeutic hypothermia (TH) and 34 term infant healthy controls (TC). Whole blood sampling was performed in the first 4 days of life, and a 14-spot ELISA Multiplex Cytokine Array was carried out on baseline samples or after stimulation with lipopolysaccharide (LPS) as an additional inflammatory stimulus. The cytokine medians were examined for differences between infants with NE and healthy TC; and then short-term outcomes of Sarnat stage, seizures, and MRI brain were examined within the NE group. The potential of LPS stimulation to predict abnormal MRI was explored using receiver operating characteristic (ROC) curves.Results: At baseline, infants with NE had significantly higher levels of erythropoietin (Epo), interleukin (IL)-6, and IL-1ra and significantly lower vascular endothelial growth factor (VEGF) than had controls. All cytokines were increased after LPS stimulation in infants with NE with an excessive Epo and IL-1ra response than in controls. Infants with NE had lower IL-8, IL-2, IL-6, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), VEGF, and interferon (IFN)-γ than controls had following LPS. GM-CSF and IFN-γ, IL-1β, IL-1ra, and VEGF were higher on days 1–2 in NE infants with abnormal neuroimaging. GM-CSF, IFN-γ, and TNF-α levels with LPS stimulation were different upon stimulation between normal and abnormal neuroimaging. TNF-α is the only strong cytokine predictor both pre- and post-LPS stimulation of abnormal brain imaging.Conclusions: Altered cytokine responses are found in infants with NE vs. controls, and more significant differences are unmasked by the additional stimulus of LPS, which potentially improves the predictive power of these cytokines for the detection of abnormal MRIs. Infants with NE undergoing TH demonstrate both trained immunity and tolerance, and understanding these responses will facilitate adjunctive immunomodulatory treatments.

show abstract

Section: Discussionsupporting

confidence: 49%

“…Inclusion criteria of infants with NE undergoing TH and healthy term control infants were enrolled in the study as per our previous publications (2,17). Neonates at risk of NE, as per Huang et al criteria (18), were recruited following informed consent and then subsequently divided into Sarnat stage for grade of NE (19).…”

Section: Study Populationmentioning

confidence: 99%

Altered Cytokine Endotoxin Responses in Neonatal Encephalopathy Predict MRI Outcomes

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Studies in human patients with stroke have shown a high number of peripheral neutrophils being associated with the severity of injury [ 71 ], as well as in neonatal HI associated with poorer neurological outcomes [ 26 ]. It has been shown that TH has a minimal effect on peripheral immune cell counts in neonatal HI cases [ 72 ]; however, HI neonates undergoing TH have altered inflammatory responses compared to healthy infants [ 73 ]. It is commonly believed that an increase in neutrophil count after HIE is possibly associated with an infection and adverse outcome; however, evidence has shown no significant changes in the neutrophil count in asphyxiated newborns [ 27 ], even less during TH [ 72 ].…”

Section: Discussionmentioning

confidence: 99%

Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia

Bernis

Zweyer

Maes

et al. 2023

IJMS

View full text Add to dashboard Cite

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.

show abstract

“…Two possible peripheral sources of purine release during and following NE include muscle tissue following increased muscle activity and systemic inflammation. While muscle activity is an unlikely source, as neonates with and without NE present similar behaviors [e.g., neonatal seizures are often accompanied by only subtle changes in behavior, further complicating their diagnosis ( Murray et al, 2016 )], there is a substantial body of evidence demonstrating altered immune responses (e.g., neutrophil activation) post-NE possibly contributing to increased purine/adenosine concentrations ( Barletta et al, 2012 ; Karmakar et al, 2016 ; Wang and Chen, 2018 ; O’Dea et al, 2020 ; Kelly et al, 2021 ). Of note, similar to increased blood purines in infants with seizures, inflammation markers are also highly associated with seizures ( Zareen et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Point-of-Care Diagnostic Method for Neonatal Encephalopathy Using Purine Nucleosides

Beamer

O’Dea

Garvey

et al. 2021

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

Background: Evidence suggests that earlier diagnosis and initiation of treatment immediately after birth is critical for improved neurodevelopmental outcomes following neonatal encephalopathy (NE). Current diagnostic tests are, however, mainly restricted to clinical diagnosis with no molecular tests available. Purines including adenosine are released during brain injury such as hypoxia and are also present in biofluids. Whether blood purine changes can be used to diagnose NE has not been investigated to date.Methods: Blood purines were measured in a mouse model of neonatal hypoxia and infants with NE using a novel point-of-care diagnostic technology (SMARTChip) based on the summated electrochemical detection of adenosine and adenosine metabolites in the blood.Results: Blood purine concentrations were ∼2–3-fold elevated following hypoxia in mice [2.77 ± 0.48 μM (Control) vs. 7.57 ± 1.41 μM (post-hypoxia), p = 0.029]. Data in infants with NE had a 2–3-fold elevation when compared to healthy controls [1.63 ± 0.47 μM (Control, N = 5) vs. 4.87 ± 0.92 μM (NE, N = 21), p = 0.0155]. ROC curve analysis demonstrates a high sensitivity (81%) and specificity (80%) for our approach to identify infants with NE. Moreover, blood purine concentrations were higher in infants with NE and seizures [8.13 ± 3.23 μM (with seizures, N = 5) vs. 3.86 ± 0.56 μM (without seizures, N = 16), p = 0.044].Conclusion: Our data provides the proof-of-concept that measurement of blood purine concentrations via SMARTChip technology may offer a low-volume bedside test to support a rapid diagnosis of NE.

show abstract

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

Cited by 5 publications

References 32 publications

Altered Cytokine Endotoxin Responses in Neonatal Encephalopathy Predict MRI Outcomes

Altered Cytokine Endotoxin Responses in Neonatal Encephalopathy Predict MRI Outcomes

Neutrophil Extracellular Traps Release following Hypoxic-Ischemic Brain Injury in Newborn Rats Treated with Therapeutic Hypothermia

Novel Point-of-Care Diagnostic Method for Neonatal Encephalopathy Using Purine Nucleosides

Contact Info

Product

Resources

About