Oxygen exposure in early life activates NLRP3 inflammasome in mouse brain

Mıçılı, Serap Cilaker; Engür, Defne; Genç, Şermin; Ercan, İlkcan; Soy, Sıla; Baysal, Bora E.; Kumral, Abdullah

doi:10.1016/j.neulet.2020.135389

Cited by 9 publications

(9 citation statements)

References 35 publications

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“…It has been reported that astrocyte, microglia and the NLRP3 inflammasome are activated in demyelination animal models [ 25 , 26 ]. Immunofluorescence staining was used to determine whether ZJU-37 alleviated demyelination by inhibiting glial activation.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have reported astrocyte and microglial activation in demyelinating diseases. The diminishing of the inflammatory response during demyelination can contribute to nervous system recovery and prevent demyelination deterioration [ 25 , 26 ]. Inflammasomes are a family of cytosolic pattern recognition receptors (PRRs) [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…The Nod-like receptor pyrin domain containing 3 (NLRP3) recruits and activates pro-caspase-1 into caspase-1 through ASC (apoptosis associated speck-like protein containing caspase recruitment domain) and then forms the inflammasome, which leads to the release of IL-1β and IL-18 into the extracellular environment and induces neuroinflammation and damage to axons [ 25 , 28 , 29 ]. It was recently verified that the NLRP3 inflammasome is overactivated during demyelinating disorders [ 26 ]. Our previous studies demonstrated that inhibition of NLRP3 inflammasome activation can alleviate demyelination in the corpus callosum induced by cuprizone [ 9 , 25 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

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A novel RIP1/RIP3 dual inhibitor promoted OPC survival and myelination in a rat neonatal white matter injury model with hOPC graft

et al. 2021

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Background The dual inhibitors of receptor interacting protein kinase-1 and -3 (RIP1 and RIP3) play an important role in cell death processes and inflammatory responses. White matter injury (WMI), a leading cause of neurodevelopmental disabilities in preterm infants, which is characterized by extensive myelination disturbances and demyelination. Neuroinflammation, leads to the loss and differentiation-inhibition of oligodendrocyte precursor cells (OPCs), represents a major barrier to myelin repair. Whether the novel RIP1/RIP3 dual inhibitor ZJU-37 can promote transplanted OPCs derived from human neural stem cells (hOPCs) survival, differentiation and myelination remains unclear. In this study, we investigated the effect of ZJU-37 on myelination and neurobehavioral function in a neonatal rat WMI model induced by hypoxia and ischemia. Methods In vivo, P3 rat pups were subjected to right common carotid artery ligation and hypoxia, and then treated with ZJU-37 or/and hOPCs, then OPCs apoptosis, myelination, glial cell and NLRP3 inflammasome activation together with cognitive outcome were evaluated at 12 weeks after transplantation. In vitro, the effect of ZJU-37 on NLRP3 inflammasome activation in astrocytes induced by oxygen–glucose deprivation (OGD) were examined by western blot and immunofluorescence. The effect of ZJU-37 on OPCs apoptosis induced by the conditioned medium from OGD-injured astrocytes (OGD-astrocyte-CM) was analyzed by flow cytometry and immunofluorescence. Results ZJU-37 combined with hOPCs more effectively decreased OPC apoptosis, promoted myelination in the corpus callosum and improved behavioral function compared to ZJU-37 or hOPCs treatment. In addition, the activation of glial cells and NLRP3 inflammasome was reduced by ZJU-37 or/and hOPCs treatment in the neonatal rat WMI model. In vitro, it was also confirmed that ZJU-37 can suppress NLRP3 inflammasome activation in astrocytes induced by OGD. Not only that, the OGD-astrocyte-CM treated with ZJU-37 obviously attenuated OPC apoptosis and dysdifferentiation caused by the OGD-astrocyte-CM. Conclusions The novel RIP1/RIP3 dual inhibitor ZJU-37 may promote OPC survival, differentiation and myelination by inhibiting NLRP3 inflammasome activation in a neonatal rat model of WMI with hOPC graft.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A novel RIP1/RIP3 dual inhibitor promoted OPC survival and myelination in a rat neonatal white matter injury model with hOPC graft

et al. 2021

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“…Caspase-1 inhibition leads to a decreased production of mature IL-1beta, which was associated with reduced infiltration of macrophages, improved alveolarization and vascular architecture, and a reduced right ventricular hypertrophy [ 47 ]. In addition to NLRP1, hyperoxia leads to activation of NLRP3 in both organs [ 106 , 107 ]. While this inflammasome was shown to play a crucial role in the development of BPD [ 106 ], its functional relevance in hyperoxia-induced brain injury remains to be investigated.…”

Section: Inflammatory Responses In Hyperoxia-induced Neonatal Lung An...mentioning

confidence: 99%

Perinatal Hyperoxia and Developmental Consequences on the Lung-Brain Axis

Obst

Herz

Alcázar

et al. 2022

Oxidative Medicine and Cellular Longevity

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Approximately 11.1% of all newborns worldwide are born preterm. Improved neonatal intensive care significantly increased survival rates over the last decades but failed to reduce the risk for the development of chronic lung disease (i.e., bronchopulmonary dysplasia (BPD)) and impaired neurodevelopment (i.e., encephalopathy of prematurity (EoP)), two major long-term sequelae of prematurity. Premature infants are exposed to relative hyperoxia, when compared to physiological in-utero conditions and, if needed to additional therapeutic oxygen supplementation. Both are associated with an increased risk for impaired organ development. Since the detrimental effects of hyperoxia on the immature retina are known for many years, lung and brain have come into focus in the last decade. Hyperoxia-induced excessive production of reactive oxygen species leading to oxidative stress and inflammation contribute to pulmonary growth restriction and abnormal neurodevelopment, including myelination deficits. Despite a large body of studies, which unraveled important pathophysiological mechanisms for both organs at risk, the majority focused exclusively either on lung or on brain injury. However, considering that preterm infants suffering from BPD are at higher risk for poor neurodevelopmental outcome, an interaction between both organs seems plausible. This review summarizes recent findings regarding mechanisms of hyperoxia-induced neonatal lung and brain injury. We will discuss common pathophysiological pathways, which potentially link both injured organ systems. Furthermore, promises and needs of currently suggested therapies, including pharmacological and regenerative cell-based treatments for BPD and EoP, will be emphasized. Limited therapeutic approaches highlight the urgent need for a better understanding of the mechanisms underlying detrimental effects of hyperoxia on the lung-brain axis in order to pave the way for the development of novel multimodal therapies, ideally targeting both severe preterm birth-associated complications.

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“…Hyperoxia can lead to the activation of nod-like receptor pyrin domain-containing-3 (NLRP3) inflammatory bodies in brain tissue, resulting in neuronal damage and cell death. [ 2 ] The increase in oxygen partial pressure in a hyperoxic environment will cause delayed development of white matter and impaired axonal conduction in mice [ 3 ] In addition, hyperoxia can damage the cells in the hippocampus, destroy the development of hippocampal neurons, affect the balance of excitatory and inhibitory nerve transmission in the hippocampus, and produce learning and cognitive impairment. [ 4 ] The cerebral vascular structure and function of mice with hyperoxia-induced experimental bronchopulmonary dysplasia (BPD) showed lifelong damage, with a long-term decline in motor and cognitive function.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of resveratrol on mitochondrial biogenesis during hyperoxia-induced brain injury in neonatal pups

et al. 2023

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Background Neonatal hyperoxic brain injury is caused by exposure to hyperphysiological oxygen content during the period of incomplete development of the oxidative stress defence system, resulting in a large number of reactive oxygen species (ROS) and causing damage to brain tissue. Mitochondrial biogenesis refers to the synthesis of new mitochondria from existing mitochondria, mostly through the PGC-1α/Nrfs/TFAM signalling pathway. Resveratrol (Res), a silencing information regulator 2-related enzyme 1 (Sirt1) agonist, has been shown to upregulate the level of Sirt1 and the expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). We speculate that Res has a protective effect on hyperoxia-induced brain injury through mitochondrial biogenesis. Methods Sprague-Dawley (SD) pups were randomly divided into the nonhyperoxia (NN) group, the nonhyperoxia with dimethyl sulfoxide (ND) group, the nonhyperoxia with Res (NR) group, the hyperoxia (HN) group, the hyperoxia with dimethyl sulfoxide (HD) group, and the hyperoxia with Res (HR) group within 12 h after birth. The HN, HD, and HR groups were placed in a high-oxygen environment (80‒85%), and the other three groups were placed in the standard atmosphere. The NR and HR groups were given 60 mg/kg Res every day, the ND and HD groups were given the same dose of dimethyl sulfoxide (DMSO) every day, and the NN and HN groups were given the same dose of normal saline every day. On postnatal day (PN) 1, PN7, and PN14, brain samples were acquired for HE staining to assess pathology, TUNEL to detect apoptosis, and real-time quantitative polymerase chain reaction and immunoblotting to detect the expression levels of Sirt1, PGC-1α, nuclear respiratory factor 1 (Nrf1), nuclear respiratory factor 2 (Nrf2) and mitochondrial transcription factor A (TFAM) in brain tissue. Results Hyperoxia induced brain tissue injury; increased brain tissue apoptosis; inhibited Sirt1, PGC-1α, Nrf1, Nrf2, TFAM mRNA expression in mitochondria; diminished the ND1 copy number and ND4/ND1 ratio; and decreased Sirt1, PGC-1α, Nrf1, Nrf2, and TFAM protein levels in the brain. In contrast, Res reduced brain injury and attenuated brain tissue apoptosis in neonatal pups and increased the levels of the corresponding indices. Conclusion Res has a protective effect on hyperoxia-induced brain injury in neonatal SD pups by upregulating Sirt1 and stimulating the PGC-1α/Nrfs/TFAM signalling pathway for mitochondrial biogenesis.

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Oxygen exposure in early life activates NLRP3 inflammasome in mouse brain

Cited by 9 publications

References 35 publications

A novel RIP1/RIP3 dual inhibitor promoted OPC survival and myelination in a rat neonatal white matter injury model with hOPC graft

A novel RIP1/RIP3 dual inhibitor promoted OPC survival and myelination in a rat neonatal white matter injury model with hOPC graft

Perinatal Hyperoxia and Developmental Consequences on the Lung-Brain Axis

Protective effect of resveratrol on mitochondrial biogenesis during hyperoxia-induced brain injury in neonatal pups

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