Inhibition of IκBβ/NFκB signaling prevents LPS-induced IL1β expression without increasing apoptosis in the developing mouse lung

McKenna, Sarah; Butler, Brittany; Jatana, Laurie; Ghosh, Sankar; Wright, Clyde J.

doi:10.1038/pr.2017.182

Cited by 17 publications

(13 citation statements)

References 43 publications

(76 reference statements)

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“…The pathogenesis of BPD is multifactorial; however, inflammation is generally believed to be the primary mediator of lung injury in preterm infants (24). Inflammatory signaling pathways, such as the TLR4 and NF-κB pathways, were indicated to be associated with BPD (21,25). The levels of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-8, are increased, and the levels of anti-inflammatory cytokines, such as IL-4, IL-10, IL-12, IL-13, and IL-18, are decreased in BPD (26,27).…”

Section: Discussionmentioning

confidence: 99%

Low-Dose Vitamin D Protects Hyperoxia-Induced Bronchopulmonary Dysplasia by Inhibiting Neutrophil Extracellular Traps

et al. 2020

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Background and Objective: As bronchopulmonary dysplasia (BPD) can lead to considerable mortality and morbidity, this disease is the focus of attention in neonatology. Vitamin D (VD), which has anti-inflammatory properties and promotes lung growth, may have a therapeutic effect on BPD. The overexpression of neutrophil extracellular traps (NETs) has been demonstrated to be involved in the pathogenesis of BPD in our previous study. This study aimed to elucidate the effect of VD on BPD and the role of NETs in this process. Methods: Newborn rats were exposed to 90% oxygen continuously for 7 days to mimic BPD, and rats under hyperoxia were injected with 1,25(OH)2D3 at different doses (0.5 ng/g, 3 ng/g). Alveolarization, pulmonary vascular development, inflammatory cytokines and NETs were assessed. Results: Hyperoxia increased mortality, decreased body weight, impaired alveolarization with a decrease in radial alveolar count (RAC) and an increase in mean linear intercept (MLI), and impaired vascular development with low vascular endothelial growth factor (VEGF) expression. Meanwhile, hyperoxia enhanced expression of the proinflammatory factors TNF-α, IL-1β, and IL-6, and elevated NETs in lung tissues and plasma. Low-dose VD (0.5 ng/g) administration increased the survival rate, attenuated developmental retardation, improved alveolarization, and pulmonary vascular development in hyperoxia-induced BPD, and reduced the expression of proinflammatory factors and NETs. However, high-dose VD (3 ng/g) treatment did not attenuate lung injury or NETs significantly, and even led to more severe developmental retardation and a higher mortality rate. Conclusions: Low-dose VD increased the survival rate, attenuated developmental retardation, and improved alveolarization and pulmonary vascularization arrest in hyperoxia-induced BPD partially by inhibiting NETs.

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Section: Discussionmentioning

confidence: 99%

Low-Dose Vitamin D Protects Hyperoxia-Induced Bronchopulmonary Dysplasia by Inhibiting Neutrophil Extracellular Traps

et al. 2020

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“…This study has a number of limitations. Specifically, only one LPS dose (5 mg/kg, IP) was used for neonatal and adult endotoxin exposure; importantly, our lab has identified this as a dose that results in ~25% mortality in neonatal mice ( 52 ); thus, it is possible that alterations in IFNβ expression and STAT1 signaling might be observed at increasingly lethal LPS doses. Additionally, samples were collected at relatively early timepoints following LPS exposure, and there may be differences in neonatal and adult IFNβ expression at later time points.…”

Section: Discussionmentioning

confidence: 99%

Immunotolerant p50/NFκB Signaling and Attenuated Hepatic IFNβ Expression Increases Neonatal Sensitivity to Endotoxemia

et al. 2018

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Sepsis is a major cause of neonatal morbidity and mortality. The current paradigm suggests that neonatal susceptibility to infection is explained by an innate immune response that is functionally immature. Recent studies in adults have questioned a therapeutic role for IFNβ in sepsis; however, the role of IFNβ in mediating neonatal sensitivity to sepsis is unknown. We evaluated the transcriptional regulation and expression of IFNβ in early neonatal (P0) and adult murine models of endotoxemia (IP LPS, 5 mg/kg). We found that hepatic, pulmonary, and serum IFNβ expression was significantly attenuated in endotoxemic neonates when compared to similarly exposed adults. Furthermore, endotoxemia induced hepatic p65/NFκB and IRF3 activation exclusively in adults. In contrast, endotoxemia induced immunotolerant p50/NFκB signaling in neonatal mice without evidence of IRF3 activation. Consistent with impaired IFNβ expression and attenuated circulating serum levels, neonatal pulmonary STAT1 signaling and target gene expression was significantly lower than adult levels. Using multiple in vivo approaches, the source of hepatic IFNβ expression in endotoxemic adult mice was determined to be the hepatic macrophage, and experiments in RAW 264.7 cells confirmed that LPS-induced IFNβ expression was NFκB dependent. Finally, treating neonatal mice with IFNβ 2 h after endotoxemia stimulated pulmonary STAT1 signaling and STAT1 dependent gene expression. Furthermore, IFNβ treatment of endotoxemic neonatal animals resulted in significantly improved survival following exposure to lethal endotoxemia. In conclusion, endotoxemia induced IFNβ expression is attenuated in the early neonatal period, secondary to impaired NFκB-p65/IRF3 signaling. Pre-treatment with IFNβ decreases neonatal sensitivity to endotoxemia. These results support further study of the role of impaired IFNβ expression and neonatal sensitivity to sepsis.

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“…Each isoform uniquely contributes to the degree and duration of NFκB activation, as well as the NFκB transcriptome. Multiple studies have implicated IκBβ in TLR4‐mediated IL1β expression 78–80,90,91 . However, this is the first report linking IκBβ to IL1 expression following CpG‐ODN TLR9‐mediated innate immune signalling.…”

Section: Discussionmentioning

confidence: 79%

“…The NFκB inhibitory protein IκBβ is particularly susceptible to alternations in intracellular calcium, as calcium‐mediated activation of calcineurin is a key step in IκBβ inactivation and subsequent NFκB activation 72,73 . The degradation kinetics of IκBα and IκBβ dictates the magnitude and duration of NFκB target gene expression, 74–77 which directly affects IL1α and IL1β expression 78–81 . Previous reports have demonstrated that exposing astrocytes 33 and pulmonary endothelial cells 82 to CpG‐ODN results in IκBα degradation, while IκBβ was not evaluated.…”

Section: Introductionmentioning

confidence: 99%

CpG‐ODN‐mediated TLR9 innate immune signalling and calcium dyshomeostasis converge on the NFκB inhibitory protein IκBβ to drive IL1α and IL1β expression

et al. 2020

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Sterile inflammation contributes to many pathological states associated with mitochondrial injury. Mitochondrial injury disrupts calcium homeostasis and results in the release of CpG-rich mitochondrial DNA. The role of CpG-stimulated TLR9 innate immune signalling and sterile inflammation is well studied; however, how calcium dyshomeostasis affects this signalling is unknown. Therefore, we interrogated the relationship besween intracellular calcium and CpG-induced TLR9 signalling in murine macrophages. We found that CpG-ODN-induced NFjB-dependent IL1a and IL1b expression was significantly attenuated by both calcium chelation and calcineurin inhibition, a finding mediated by inhibition of degradation of the NFjB inhibitory protein IjBb. In contrast, calcium ionophore exposure increased CpG-induced IjBb degradation and IL1a and IL1b expression. These results demonstrate that through its effect on IjBb degradation, increased intracellular Ca 2+ drives a pro-inflammatory TLR9-mediated innate immune response. These results have implications for the study of innate immune signalling downstream of mitochondrial stress and injury.

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Inhibition of IκBβ/NFκB signaling prevents LPS-induced IL1β expression without increasing apoptosis in the developing mouse lung

Cited by 17 publications

References 43 publications

Low-Dose Vitamin D Protects Hyperoxia-Induced Bronchopulmonary Dysplasia by Inhibiting Neutrophil Extracellular Traps

Low-Dose Vitamin D Protects Hyperoxia-Induced Bronchopulmonary Dysplasia by Inhibiting Neutrophil Extracellular Traps

Immunotolerant p50/NFκB Signaling and Attenuated Hepatic IFNβ Expression Increases Neonatal Sensitivity to Endotoxemia

CpG‐ODN‐mediated TLR9 innate immune signalling and calcium dyshomeostasis converge on the NFκB inhibitory protein IκBβ to drive IL1α and IL1β expression

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