Deficiency of receptor-interacting protein kinase 3 (RIPK3) attenuates inflammation and organ injury in neonatal sepsis

Laura W. Hansen, Asha Jacob, Weng Lang Yang, Alexandra C. Bolognese, Jose Prince, Jeffrey M. Nicastro, Gene F. Coppa, Ping Wang

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Introduction: Sepsis is the third leading cause of morbidity and mortality in neonates. Sepsis in neonates is characterized as the systemic inflammation owing to infection within the first 28 days after birth. The molecular mechanism causing the exaggerated inflammation phenotype in neonates has not been completely elucidated. Receptor interacting protein kinase 3 (RIPK3) is a protein identified as a mediator in programmed necrosis or necroptosis. We hypothesize that RIPK3 could be responsible for the inflammatory response in neonates and that deficiency in the RIPK3 protein attenuates inflammation and organ injury in neonatal sepsis. Methods: Male and female C57BL6 wild-type (WT) and RIPK3 knock-out (KO) newborn mice aged 5–7 days (3–4 g body weight) were injected intraperitoneally with 0.9 mg/g cecal slurry (CS). At 10 h after injection, the newborns were euthanized and blood, the lungs and gut tissues were collected. Results: At 10 h after CS injection, serum cytokines IL-6 and IL-1β in the WT mice were increased by 511- and 43-fold whereas in KO mice, these levels were increased by 166-fold and 22-fold, respectively. Lung IL-1β in the WT mice increased by 7-fold after CS injection whereas only a 4-fold increase was seen in the KO mice. In the lungs of CS injected KO mice, the injury score, MIP-2 mRNA, myeloperoxidase (MPO) activity and TUNEL staining were significantly reduced by 76%, 70%, 26% and 74%, respectively compared to the CS WT mice. Gut TUNEL staining was also reduced by 80%. Conclusion: The deficiency in RIPK3 attenuated serum and lung cytokines, lung injury and neutrophil infiltration and lung and gut apoptosis. These data suggest that RIPK3, in part, is responsible for the systemic inflammatory response in neonatal sepsis.

Original languageEnglish (US)
Pages (from-to)1699-1705
Number of pages7
JournalJournal of Pediatric Surgery
Volume53
Issue number9
DOIs
StatePublished - Sep 2018
Externally publishedYes

Keywords

  • Apoptosis
  • Cytokines
  • Lung injury
  • Neonatal sepsis
  • RIPK3

ASJC Scopus subject areas

  • Surgery
  • Pediatrics, Perinatology, and Child Health

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