Emerging Role of the NLRP3 Inflammasome and Interleukin-1β in Neonates

Omer, Murwan; Melo, Ashanty M; Kelly, Lynne; Dermott, Emma Jane Mac; Leahy, Timothy Ronan; Killeen, Orla; Saugstad, Ola Didrik; Savani, Rashmin C.; Molloy, Eleanor J.

doi:10.1159/000507584

Cited by 20 publications

(13 citation statements)

References 106 publications

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“…Oxygen-mediated effects on choroidal thinning may occur via the release of inflammatory factors such as interleukins, which have been shown to mediate neuroinflammation in neonates. 24,25 Limitations of our study include a relatively small number of subjects and a wide range of PMAs at the time of imaging. However, strengths of the study include standardized NICU protocols on oxygen use, carefully acquired oxygen data across a range of PMAs spanning early and later stages of ROP, and high-quality images on an arm-mounted spectraldomain OCT device.…”

Section: Discussionmentioning

confidence: 99%

Early Postnatal Oxygen Exposure Predicts Choroidal Thinning in Neonates

Pettenkofer

Nittala

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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To evaluate whether choroidal thickness (CT) using arm-mounted optical coherence tomography (OCT) in infants screened for retinopathy of prematurity (ROP) correlates with oxygen exposure in neonates. METHODS.OCT images were obtained in infants screened for ROP in a single level IV neonatal intensive care unit. CT was measured at three different locations: the subfoveal center and 1.5 mm from the fovea center in each direction. Correlation and regression analyses were performed to determine the relationship between clinical factors and CT. Clinical factors included gestational age, birth weight, presence of bronchopulmonary dysplasia (BPD), and fraction of inspired oxygen (FiO 2 ) at defined time points: 30 weeks postmenstrual age (PMA), 36 weeks PMA, and on day of imaging. RESULTS.Mean subfoveal, nasal, and temporal choroidal thicknesses CT (SFCT, NCT, and TCT, respectively) were 228.0 ± 51.4 μm, 179.7 ± 50.3 μm, and 186.4 ± 43.8 μm, respectively. SFCT was found to be significantly thicker than NCT and TCT (P < 0.0001 and P = 0.0002, respectively), but no significant difference was found between NCT and TCT (P = 0.547). Compared with infants without BPD, infants with BPD had thinner SFCT and NCT (P = 0.01 and P = 0.0008, respectively). Birth weight was positively correlated with SFCT (r = 0.39, P = 0.01) and NCT (r = 0.33, P = 0.045) but not TCT. Gestational age and ROP stage were not significantly associated with CT. SFCT was found to be significantly thinner with higher average FiO 2 supplementation levels at 30 weeks PMA (r = -0.51, P = 0.01) but not at 36 weeks PMA. Regression analysis revealed that FiO 2 at 30 weeks PMA was an independent predictor of SFCT in infants screened for ROP (P = 0.01). CONCLUSIONS.Early postnatal exposure (<32 weeks PMA) to higher oxygen supplementation in premature neonates statistically predicts choroidal thinning.

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Section: Discussionmentioning

confidence: 99%

Early Postnatal Oxygen Exposure Predicts Choroidal Thinning in Neonates

Pettenkofer

Nittala

et al. 2021

Invest. Ophthalmol. Vis. Sci.

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“…In the central nervous system, the IL-18 and IL-1 β receptors are expressed on the nerve cell surface, and an increase in these proinflammatory cytokines has been observed in cerebrospinal fluids of infants with HIE [ 50 ]. IL-1 β may induce neuronal injury through various mechanisms, including the induction of nitric oxide production, activation of necrotic and apoptotic pathways, modulation of synaptic plasticity, and effects on components of the mitogen-activated protein kinase pathway, which controls neurodegeneration [ 51 ]. Here, we found that treatment with neferine significantly reduced NLRP3 inflammasome activation and inhibited ASC, GSDMD, and cleaved caspase-1 activation, thereby reducing IL-1 β and IL18 expression in the HIBD rat model.…”

Section: Discussionmentioning

confidence: 99%

Neferine Protects against Hypoxic‐Ischemic Brain Damage in Neonatal Rats by Suppressing NLRP3‐Mediated Inflammasome Activation

Zhu

Huang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Hypoxic-ischemic encephalopathy (HIE) is recognized as the main cause of neonatal death, and efficient treatment strategies remain limited. Given the prevalence of HIE and the associated fatality, further studies on its pathogenesis are warranted. Oxidative stress and neuroinflammatory injury are two important factors leading to brain tissue injury and nerve cell loss in HIE. Neferine, an alkaloid extracted from lotus seed embryo, exerts considerable effects against several diseases such as cancers and myocardial injury. In this study, we demonstrated the neuroprotective effect of neferine on HIE and hypothesized that it involves the inhibition of neuronal pyroptosis, thereby ameliorating neurological inflammation and oxidative stress. We demonstrated that the mRNA levels of proteins associated with pyroptosis including caspase-1, the caspase adaptor ASC, gasdermin D, interleukin- (IL-) 18, IL-1β, and some inflammatory factors were significantly increased in neonatal HIBD model rats compared to those in the control group. The increase in these factors was significantly suppressed by treatment with neferine. We stimulated PC12 cells with CoCl2 to induce neuronal HIBD in vitro and investigated the relationship between neferine and pyroptosis by altering the expression of the NLRP3 inflammasome. The overexpression of NLRP3 partially reversed the neuroprotective effect of neferine on HIBD, whereas NLRP3 knockdown further inhibited caspase-1 activation and IL-1β and IL18 expression. In addition, simultaneous alteration of NLRP3 expression induced changes in intracellular oxidative stress levels after HIBD. These findings indicate that neferine ameliorates neuroinflammation and oxidative stress injury by inhibiting pyroptosis after HIBD. Our study provides valuable information for future studies on neferine with respect to neuroinflammation and pyroptosis.

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“…Brain MRI can help determine occurrence of injury, but is only possible between 7 and 10 days after birth, i.e., outside the therapeutic window. Circulating inflammation makers such as cytokines ( Chaparro-Huerta et al, 2017 ; Omer et al, 2020 ; Sweetman et al, 2020 ) or microRNAs ( O’Sullivan et al, 2019 ), have shown great promise as novel diagnostic tools to support the identification of infants with NE. Analyzing these markers requires, however, sample preparation and, in some cases, equipment which is not suited for use in the NICU.…”

Section: Discussionmentioning

confidence: 99%

“…Several circulating biomarkers are currently under investigation ( Graham et al, 2018 ). Among these, alterations in microRNA levels in umbilical cord blood ( O’Sullivan et al, 2019 ) and elevations of pro-inflammatory cytokines in the blood ( Chaparro-Huerta et al, 2017 ; Omer et al, 2020 ; Sweetman et al, 2020 ) have shown promising results. Detection techniques for these molecules do not support a fast diagnosis, requiring sample preparation and sophisticated equipment [e.g., enzyme-linked immunosorbent assays (cytokines) and qPCR (microRNA)], potentially delaying the diagnosis past the ideal therapeutic window of < 6 h post-delivery.…”

Section: Introductionmentioning

confidence: 99%

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

Beamer

O’Dea

Garvey

et al. 2021

Front. Mol. Neurosci.

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Background: Evidence suggests that earlier diagnosis and initiation of treatment immediately after birth is critical for improved neurodevelopmental outcomes following neonatal encephalopathy (NE). Current diagnostic tests are, however, mainly restricted to clinical diagnosis with no molecular tests available. Purines including adenosine are released during brain injury such as hypoxia and are also present in biofluids. Whether blood purine changes can be used to diagnose NE has not been investigated to date.Methods: Blood purines were measured in a mouse model of neonatal hypoxia and infants with NE using a novel point-of-care diagnostic technology (SMARTChip) based on the summated electrochemical detection of adenosine and adenosine metabolites in the blood.Results: Blood purine concentrations were ∼2–3-fold elevated following hypoxia in mice [2.77 ± 0.48 μM (Control) vs. 7.57 ± 1.41 μM (post-hypoxia), p = 0.029]. Data in infants with NE had a 2–3-fold elevation when compared to healthy controls [1.63 ± 0.47 μM (Control, N = 5) vs. 4.87 ± 0.92 μM (NE, N = 21), p = 0.0155]. ROC curve analysis demonstrates a high sensitivity (81%) and specificity (80%) for our approach to identify infants with NE. Moreover, blood purine concentrations were higher in infants with NE and seizures [8.13 ± 3.23 μM (with seizures, N = 5) vs. 3.86 ± 0.56 μM (without seizures, N = 16), p = 0.044].Conclusion: Our data provides the proof-of-concept that measurement of blood purine concentrations via SMARTChip technology may offer a low-volume bedside test to support a rapid diagnosis of NE.

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Emerging Role of the NLRP3 Inflammasome and Interleukin-1β in Neonates

Cited by 20 publications

References 106 publications

Early Postnatal Oxygen Exposure Predicts Choroidal Thinning in Neonates

Early Postnatal Oxygen Exposure Predicts Choroidal Thinning in Neonates

Neferine Protects against Hypoxic‐Ischemic Brain Damage in Neonatal Rats by Suppressing NLRP3‐Mediated Inflammasome Activation

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

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