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Neonatology. 2019 Mar 25;115(4):355-362. doi: 10.1159/000497200. [Epub ahead of print]

Neuromodulatory Effect of NLRP3 and ASC in Neonatal Hypoxic Ischemic Encephalopathy.

Author information

1
Department of Pediatric Research, Clinic of Women and Child Health, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway, maryst@rr-research.no.
2
Department of Clinical and Molecular Medicine, Norwegian University of Technology and Science, Trondheim, Norway.
3
Department of Laboratory Medicine, St Olavs Hospital, Trondheim, Norway.
4
Department of Microbiology, Oslo University Hospital and University of Oslo, Oslo, Norway.
5
Research Institute of Internal Medicine, Rikshospitalet, Oslo University Hospital, Oslo, Norway.
6
Department of Pediatric Research, Clinic of Women and Child Health, Oslo University Hospital, Rikshospitalet and University of Oslo, Oslo, Norway.
7
K.G Jebsen Inflammation Research Centre and Faculty of Medicine and University of Oslo, Oslo, Norway.

Abstract

BACKGROUND:

Following birth asphyxia there is a robust inflammatory response. NLRP3 is a receptor of the innate immune system. Upon activation, NLRP3 forms an inflammasome together with ASC and procaspase-1 to mediate release of IL-1β and IL-18. NLRP3 has previously been shown to be upregulated following neonatal hypoxic-ischemic (HI) brain injury in mice, but with no early effect on brain injury.

OBJECTIVE:

We aimed to evaluate if deficiency of NLRP3 or ASC protects against neonatal HI brain damage 7 days after hypoxia-ischemia.

METHODS:

C57BL/6J, NLRP3-/-, and ASC-/- mice were subjected to unilateral common carotid artery ligation followed by hypoxia at P9. Brain infarction, apoptosis, and microglial response were evaluated, as well as total RNA sequencing and examination of plasma levels of systemic proinflammatory cytokines.

RESULTS:

NLRP3-/- mice showed significantly increased brain infarction volumes compared to wild-type (Wt) mice, while ASC-/- mice showed reduced brain infarction volumes after neonatal hypoxia-ischemia. The amount of activated microglia was increased in NLRP3-/- mice, while decreased in ASC-/- mice compared to Wt mice. Total RNA sequencing showed an impaired inflammatory transcriptional response in the hippocampus of NLRP3-/- mice. Plasma levels of IL-1β and IL-18 were not affected, but TNF was lower in NLRP3-/- and ASC-/- mice compared to Wt mice.

CONCLUSION:

ASC deficiency is neuroprotective in neonatal HI brain damage in mice, while NLRP3 deficiency increases brain damage.

KEYWORDS:

Brain injury; Hypoxia-ischemia; Hypoxic-ischemic brain injury; Inflammation; Mice; Newborn brain; Perinatal asphyxia; Perinatal brain damage

PMID:
30909283
DOI:
10.1159/000497200

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