Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

Vodret, Simone; Bortolussi, Giulia; Jašprová, Jana; Vı́tek, Libor; Muro, Andrés F.

doi:10.1186/s12974-017-0838-1

Cited by 38 publications

(43 citation statements)

References 71 publications

(107 reference statements)

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“…Additionally, IL-1β induced a fast increase in extracellular glutamate contents, which affected the excitotoxicity of cells exposed to glutamate, leading to neural damage [ 48 ]. However, the pro-inflammatory cytokines activated by the MAPK signaling pathway and NF-κB signaling pathway via binding to IL-1 receptor 1 recruit more cytokines and immune cells, resulting in deleterious cell injury [ 5 , 6 , 20 , 34 , 35 ]. In the present study, IL-1β and IL-18 expression increased in UCB-treated astrocytes, whereas VX-765 could prevent this inflammatory cascade and inhibit the activation of caspase-1.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have demonstrated that elevated levels of UCB activated astrocytes and microglia, as well as gliosis, with a subsequent upregulation of inflammatory markers, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 [ 15 – 18 ]. In turn, the increased cytokines could further exacerbate nerve cell death and inflammatory responses by activating the MAPK and nuclear factor-kappaB (NF-κB) signaling cascades [ 17 , 19 , 20 ]. Interestingly, blocking pro-inflammatory cytokine production decreased UCB-induced cell death, either by the loss of membrane integrity or by apoptosis [ 7 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Unconjugated bilirubin induces pyroptosis in cultured rat cortical astrocytes

Feng

Qian

et al. 2018

J Neuroinflammation

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BackgroundBilirubin-induced neurological dysfunction (BIND), a severe complication of extreme neonatal hyperbilirubinemia, could develop into permanent neurodevelopmental impairments. Several studies have demonstrated that inflammation and nerve cell death play important roles in bilirubin-induced neurotoxicity; however, the underlying mechanism remains unidentified.MethodsThe present study was intended to investigate whether pyroptosis, a highly inflammatory form of programmed cell death, participated in the bilirubin-mediated toxicity on cultured rat cortical astrocytes. Further, VX-765, a potent and selective competitive drug, was used to inhibit the activation of caspase-1. The effects of VX-765 on astrocytes treated with bilirubin, including the cell viability, morphological changes of the cell membrane and nucleus, and the production of pro-inflammation cytokines, were observed.ResultsStimulation of the astrocytes with unconjugated bilirubin (UCB) at the conditions mimicking those of jaundiced newborns significantly increased the activation of caspase-1. Further, caspase-1 activation was inhibited by treatment with VX-765. Compared with UCB-treated astrocytes, the relative cell viability of VX-765-pretreated astrocytes was improved; meanwhile, the formation of plasma membrane pores was prevented, as measured by lactate dehydrogenase release, trypan blue staining, and ethidium bromide (EtBr) uptake. Moreover, DNA fragmentation was partly attenuated and the release of IL-1β and IL-18 was apparently decreased.ConclusionPyroptosis is involved in the process of UCB-induced rat cortical astrocytes’ injury in vitro and may be the missing link of cell death and inflammatory response exacerbating UCB-related neurotoxicity. More importantly, the depression of caspase-1 activation, the core link of pyroptosis, attenuated UCB-induced cellular dysfunction and cytokine release, which might shed light on a new therapeutic approach to BIND.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unconjugated bilirubin induces pyroptosis in cultured rat cortical astrocytes

Feng

Qian

et al. 2018

J Neuroinflammation

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“…qRT-PCR experiments were performed as previously described (Bockor et al, 2017;Vodret et al, 2017). Briefly, total RNA from mouse livers was prepared using EuroGOLD Trifast (Euroclone, Milano, Italy).…”

Section: Mrna Quantification Analysis (Qrt-pcr)mentioning

confidence: 99%

Promoterless gene targeting without nucleases rescues lethality of a Crigler‐Najjar syndrome mouse model

et al. 2017

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Crigler‐Najjar syndrome type I (CNSI) is a rare monogenic disease characterized by severe neonatal unconjugated hyperbilirubinemia with a lifelong risk of neurological damage and death. Liver transplantation is the only curative option, which has several limitations and risks. We applied an in vivo gene targeting approach based on the insertion, without the use of nucleases, of a promoterless therapeutic cDNA into the albumin locus of a mouse model reproducing all major features of CNSI. Neonatal transduction with the donor vector resulted in the complete rescue from neonatal lethality, with a therapeutic reduction in plasma bilirubin lasting for at least 12 months, the latest time point analyzed. Mutant mice, which expressed about 5–6% of WT Ugt1a1 levels, showed normal liver histology and motor‐coordination abilities, suggesting no functional liver or brain abnormalities. These results proved that the promoterless gene therapy is applicable for CNSI, providing therapeutic levels of an intracellular ER membrane‐bound enzyme responsible for a lethal liver metabolic disease.

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“…Here we have developed a new animal model of bilirubin toxicity and investigated the consequences of this toxicity in the auditory brainstem, which is associated with hearing loss. The most commonly used animal model of hyperbilirubinaemia is the Gunn rat and Ugt1 -/- mice [ 24 , 47 , 48 ]. Gunn rats having been administered sulfadimethoxine (to displace endogenous bound bilirubin from albumin) have been used to investigate bilirubin toxicity [ 6 , 21 , 23 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroinflammation and ER-stress are key mechanisms of acute bilirubin toxicity and hearing loss in a mouse model

et al. 2018

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Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin–a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversi...

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Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

Cited by 38 publications

References 71 publications

Unconjugated bilirubin induces pyroptosis in cultured rat cortical astrocytes

Unconjugated bilirubin induces pyroptosis in cultured rat cortical astrocytes

Promoterless gene targeting without nucleases rescues lethality of a Crigler‐Najjar syndrome mouse model

Neuroinflammation and ER-stress are key mechanisms of acute bilirubin toxicity and hearing loss in a mouse model

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