Altered inflammasome activation in neonatal encephalopathy persists in childhood

Abstract

Neonatal encephalopathy (NE) is characterized by altered neurological function in term infants and inflammation plays an important pathophysiological role. Inflammatory cytokines interleukin (IL)-1β, IL-1ra and IL-18 are activated by the nucleotide-binding and oligomerization domain (NOD)-, leucine-rich repeat domain (LRR)-and NOD-like receptor protein 3 (NLRP3) inflammasome; furthermore, we aimed to examine the role of the inflammasome multiprotein complex involved in proinflammatory responses from the newborn period to childhood in NE. Cytokine concentrations were measured by multiplex enzyme-linked immunosorbent assay (ELISA) in neonates and children with NE in the absence or presence of lipopolysaccharide (LPS) endotoxin. We then investigated expression of the NLRP3 inflammasome genes, NLRP3, IL-1β and ASC by polymerase chain reaction (PCR). Serum samples from 40 NE patients at days 1 and 3 of the first week of life and in 37 patients at age 4-7 years were analysed. An increase in serum IL-1ra and IL-18 in neonates with NE on days 1 and 3 was observed compared to neonatal controls. IL-1ra in NE was decreased to normal levels at school age, whereas serum IL-18 in NE was even higher at school age compared to school age controls and NE in the first week of life. Percentage of LPS response was higher in newborns compared to school-age NE. NLRP3 and IL-1β gene expression were up-regulated in the presence of LPS in NE neonates and NLRP3 gene expression remained up-regulated at school age in NE patients compared to controls. Increased inflammasome activation in the first day of life in NE persists in childhood, and may increase the window for therapeutic intervention.

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

“…Understanding the role of cytokines in the evolution of neonatal brain injury, as well as the dynamic nature of cytokine release after a hypoxic-ischemic insult, is a promising avenue for identifying biomarkers of ongoing brain injury in newborns with antenatal/postnatal infection/inflammation following HI, especially those that do not show an improved outcome after TH [84,[104][105][106][107].…”

Platelets in pediatric and neonatal sepsis: novel mediators of the inflammatory cascade

“…52 In neonatal studies, NLRP3 has been studied predominantly in the context of hypoxic ischaemic encephalopathy and chronic lung disease rather than sepsis in serum as opposed to in platelets. 56,57 Other inflammasomes have received even less attention. 58 The presence of NLRP3 in platelets is likely to be a topic of for future debate.…”

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

“…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 ).…”