Abstract
Neonatal hypoxic-ischemic encephalopathy (HIE) often leads to neonatal death or severe, irreversible neurological deficits. Pathologically, the occurrence of massive cell death and subsequent inflammation suggested that pyroptosis, an inflammation associated programed cell death, might play a role in HIE. Here, by measuring changes of key molecules in pyroptosis pathway in HIE patients, we discovered that their elevation levels tightly correlate with the severity of HIE. Next, we demonstrated that application of MCC950, a small molecule to inhibit NLRP3 inflammasome and thus pyroptosis, substantially alleviated pyroptosis and the injury severity in rats with neonatal hypoxic-ischemic brain damage (HIBD). Mechanistically, we showed that NLRP-3/caspase-1/GSDMD axis is required for microglia pyroptosis and activation. Our data demonstrated that microglia mediated pyroptosis played a crucial role in neonatal HIE, which shed lights into the development of intervention avenues targeting pyroptosis to treat HIE and traumatic brain injuries.
Keywords:
Hypoxic-ischemic brain damage; MCC950; Microglia; NLRP-3; Neonatal; Pyroptosis.
Copyright © 2019 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Animals, Newborn
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Case-Control Studies
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Caspase 1 / blood
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Caspase 1 / genetics
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Caspase 1 / metabolism
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Disease Models, Animal
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Female
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Furans
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Hypoxia-Ischemia, Brain / blood
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Hypoxia-Ischemia, Brain / metabolism
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Hypoxia-Ischemia, Brain / pathology*
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Indenes
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Infant, Newborn
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Inflammasomes / drug effects
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Inflammasomes / metabolism
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Interleukin-1beta / blood
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Interleukin-1beta / genetics
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Interleukin-1beta / metabolism
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Intracellular Signaling Peptides and Proteins / blood
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Microglia / metabolism*
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Microglia / pathology
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NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
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NLR Family, Pyrin Domain-Containing 3 Protein / blood
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NLR Family, Pyrin Domain-Containing 3 Protein / genetics
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NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
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Phosphate-Binding Proteins / blood
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Phosphate-Binding Proteins / genetics
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Phosphate-Binding Proteins / metabolism
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Pyroptosis / drug effects
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Pyroptosis / physiology
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Rats, Sprague-Dawley
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Sulfonamides
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Sulfones / pharmacology
Substances
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Furans
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GSDMD protein, human
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Gsdmd protein, rat
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Heterocyclic Compounds, 4 or More Rings
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IL1B protein, human
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Indenes
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Inflammasomes
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Interleukin-1beta
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Intracellular Signaling Peptides and Proteins
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NLR Family, Pyrin Domain-Containing 3 Protein
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NLRP3 protein, human
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Nlrp3 protein, rat
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Phosphate-Binding Proteins
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Sulfonamides
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Sulfones
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N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
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Caspase 1