Blocking macrophage migration inhibitory factor activity alleviates mouse acute otitis media in vivo

Zhang, Jin; Xu, Min; Zheng, Qing Yin; Zhang, Yan; Ma, Weijun; Zhang, Zhaoqiang

doi:10.1016/j.imlet.2014.07.013

Cited by 17 publications

(16 citation statements)

References 24 publications

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“…We also investigated the effect of LPS on hearing and the auditory brainstem. This showed a significant rise in the ABR threshold (from 39±2 dB SPL for control n = 5 to 50±7 dB SPL after LPS n = 4, P = 0.014, Fig 4B–4D ) and corroborated previous data on the effect of LPS or bacterial infection on the auditory system in other animal models [ 39 – 42 ]. The rise in ABR threshold caused by LPS was smaller than that produced by bilirubin (compare Fig 2D with Fig 4C ) but the broader similarity is consistent with bilirubin toxicity producing neuro-inflammation to which the auditory brainstem is particularly sensitive.…”

Section: Resultssupporting

confidence: 91%

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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Section: Resultssupporting

confidence: 91%

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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“…Acute otitis media could develop into otitis media chronically, leading to hearing loss ( 1 , 29 ). Severe complications include language disability and intellectual impairment ( 30 ). However, until now the specific molecular mechanism of acute otitis media is poorly known, and finding effective therapeutic strategy is urgently required.…”

Section: Discussionmentioning

confidence: 99%

Fisetin administration improves LPS-induced acute otitis media in mouse in vivo

Chen

Huang

2018

Int J Mol Med

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Acute otitis media is one of the most common infectious diseases worldwide in spite of the widespread vaccination. The present study was conducted to explore the effects of fisetin on mouse acute otitis media models. The animal models were established by lipopolysaccharide (LPS) injection into the middle ear of mice via the tympanic membrane. Fisetin was administered to mice for ten days through intragastric administration immediate after LPS application. Hematoxylin and eosin (H&E) staining was performed and the pro-inflammatory cytokines, including interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-6 and VEGF, were measured through enzyme-linked immunosorbent assay (ELISA) method and RT-qPCR analysis. Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway was detected by immunoblotting assays. Reactive oxygen species (ROS) generated levels were determined through assessment of anti-oxidants, and TXNIP/MAPKs signaling pathways were explored to reveal the possible molecular mechanism for acute otitis media progression and the function of fisetin. Fisetin reduced mucosal thickness caused by LPS. In fisetin-treated animals, pro-inflammatory cytokine release was downregulated accompanied with TLR4/NF-κB inactivation. ROS production was significantly decreased in comparison to the LPS-treated group. The TXNIP/MAPKs signaling pathway was inactivated for fisetin treatment in LPS-induced mice with acute otitis media. The above results indicated that fisetin improved acute otitis media through inflammation and ROS suppression via inactivating TLR4/NF-κB and TXNIP/MAPKs signaling pathways.

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“…Last but not least, in our current work, we provided evidence that elevated Irg1 could decoy macrophage to suppress oxidative stress and streptococcus pneumoniae infection through activation of Nrf2 signaling pathway in response to increased expression of Nrf2, Hmox1 and SOD and decreased expression of MDA and NO. The reduction in activity of macrophage migration inhibitory factor can relieve mouse AOM in vivo [33]. MDA is a final product of lipid peroxidation associated with oxidative stress, and NO is an extremely diffusible molecule that can establish firm oxidized metabolites [34].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of immune-responsive gene 1 prevents acute otitis media due to streptococcus pneumoniae infection through Nrf2- Hmox1 pathway

Yang

Wang

et al. 2019

Preprint

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Background: Acute otitis media (AOM) is one of the most commonly diagnosed childhood diseases that are associated with influenza infection. Immunoresponsive gene 1 (Irg1) is overexpressed in mammalian macrophage during inflammation process. Here, the present study aims to investigate the role of Irg1 in streptococcus pneumoniae infection-induced inflammatory response in AOM through Nrf2 signaling pathway. Methods: Positive rate of streptococcus pneumoniae and expression of Irg1, Nrf2 and Hmox1 were determined in the middle ear lavage fluid from 85 AOM patients infected with streptococcus pneumoniae and 48 healthy subjects. After the successful establishment of mice model with AOM, macrophage was harvest from the middle ear lavage fluid of mice. At last, to investigate the effect of Irg1 and Nrf2 signaling pathway on inflammatory response and streptococcus pneumoniae infection by accumulating macrophage, Irg1, sh-Irg1 and retinoic acid (an inhibitor of Nrf2 signaling pathway) were injected into AOM mice. Results: Irg1 exhibited a high level and activated Nrf2 signaling pathway was detected in AOM. Besides, positive rate of streptococcus pneumoniae was increased in AOM. Furthermore, in the mice model with AOM, Irg1 could repress inflammatory response by downregulating expression of TNF-α, IL-6 and IL-1β and inhibit streptococcus pneumoniae infection by stimulating accumulation of macrophage to increase its endocytosis through activation of Nrf2 signaling pathway. Conclusion: Taken together, Irg1 contributes to inhibiting inflammatory response and streptococcus pneumoniae infection in AOM by promoting accumulation of macrophage through activation of Nrf2 signaling pathway, which provides novel therapeutic targets for AOM therapy.

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Blocking macrophage migration inhibitory factor activity alleviates mouse acute otitis media in vivo

Cited by 17 publications

References 24 publications

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

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

Fisetin administration improves LPS-induced acute otitis media in mouse in vivo

Overexpression of immune-responsive gene 1 prevents acute otitis media due to streptococcus pneumoniae infection through Nrf2- Hmox1 pathway

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