Cold‐inducible RNA‐binding protein contributes to intracerebral hemorrhage‐induced brain injury via TLR4 signaling

Zhou, Kai; Cui, Shengtao; Duan, Wei; Zhang, Jianrong; Huang, Jiacheng; Wang, Li; Gong, Zhihua; Zhou, Yu

doi:10.1002/brb3.1618

Cited by 15 publications

(9 citation statements)

References 21 publications

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“…CIRP can bind to the TLR4 to activate the nuclear factor κB (NF-κB) signaling (Chen et al, 2016;Zhou et al, 2020), which induces the expression of NLRP3, pro-IL-1β and many other cytokines, leading to activation of NLRP3 inflammasome (Schroder and Tschopp, 2010;Wang et al, 2018;Yu et al, 2017). The activation of NLRP3 inflammasome will deteriorate inflammation of pancreatitis (Hou et al, 2019;Sendler et al, 2020), and esults in production of IL-1β, IL-18 (Fan and Fan, 2018), and HMGB1 (Hou et al, 2018), which are associated with systemic injury.…”

Section: Discussionmentioning

confidence: 99%

Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1β/CXCL1 Signaling

Wang

Guo

et al. 2021

Front. Pharmacol.

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Objective: Severe acute pancreatitis (SAP) can lead to acute lung injury (ALI). This study investigated the therapeutic effect of emodin and its molecular mechanisms in a rat model of SAP-ALI.Methods: Forty male Sprague-Dawley rats were randomly divided into the groups: Control (CON), SAP (SAP), emodin (EMO), and C23 (C23). The latter three groups of rats were induced for SAP-ALI by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct and were treated with vehicle, emodin or C23, respectively. One day post induction, their pancreatic and lung injury was assessed by histology and arterial blood gas analysis. In vitro, rat alveolar macrophages (NR8383 cells) were treated with recombinant rat CIRP in the presence or absence of TAK242 (a TLR4 inhibitor), C23 or emodin. The CIRP-mediated activation of the NLRP3/IL-1β/CXCL1 signaling in rat lungs and NR8383 cells was determined. Similarly, the role of IL-1β in the CIRP-induced CXCL1 expression was investigated.Results: Emodin treatment significantly reduced inflammation and tissue damages in the pancreatic and lung tissues in rats with SAP-ALI, accompanied by decreasing serum amylase, CIRP and IL-1β levels and improving lung function. Furthermore, emodin significantly mitigated the SAP-up-regulated CIRP expression in the pancreatic islets and lung tissues, and attenuated the SAP-activated NF-κB signaling, NLRP3 inflammasome formation and CXCL1 expression in lung resident macrophages as well as neutrophil infiltration in the lungs of rats. In addition, treatment with CIRP significantly activated the NF-κB signaling and NLRP3 inflammasome formation and induced IL-1β and CXCL1 expression and pyroptosis in NR8383 cells, which were abrogated by TAK242 and significantly mitigated by C23 or emodin. Moreover, CIRP only induced very lower levels of CXCL1 expression in IL-1β-silencing NR8383 cells and treatment with IL-1β induced CXCL1 expression in NR8383 cells in a dose and time-dependent manner.Conclusion: Emodin may inhibit the CIRP-activated NLRP3/IL-1β/CXCL1signaling to decrease neutrophil infiltration and ameliorate the SAP-ALI in rats.

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Section: Discussionmentioning

confidence: 99%

Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1β/CXCL1 Signaling

Wang

Guo

et al. 2021

Front. Pharmacol.

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“…Previous studies have reported that TLR4 is highly expressed in necrotizing enterocolitis (42), oral cancer and brain injury (43). Of note, TLR4 is also highly expressed in AOM (31,44).…”

Section: Discussionmentioning

confidence: 90%

Long non‑coding RNA NEAT1 contributes to lipopolysaccharide‑induced inflammation and apoptosis of human middle ear epithelial cells via regulating the miR‑301b‑3p/TLR4 axis

et al. 2021

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Acute otitis media (AOM) is a common infectious disease in children that is accompanied by signs and symptoms of middle ear inflammation and infection. Previous studies have shown that the long non-coding (lnc)RNA nuclear-enriched abundant transcript 1(NEAT1) participates in various inflammatory conditions and plays an important regulatory role. The focus of the present study was the biological function of NEAT1 and underlying molecular mechanism in lipopolysaccharide (LPS)-induced human middle ear epithelial cells (HMEECs). The expression of NEAT1, miR-301b-3p and toll-like receptor 4 (TLR4) protein were determined by reverse transcription-quantitative PCR and western blot assays, respectively. Dual-luciferase reporter assay was performed to investigate the combination of miR-301b-3p and NEAT1 or TLR4. In addition, cell viability, apoptosis and the levels of pro-inflammatory factors (IL-1β, TNF-α and IL-6) were measured by Cell Counting Kit-8 assay, flow cytometry and ELISA, respectively. Cell viability was significantly decreased, whereas apoptosis and inflammation were increased in LPS-stimulated HMEECs. Functional analyses demonstrated that NEAT1 was upregulated following LPS treatment, whereas knockdown of NEAT1 significantly increased cell viability and alleviated apoptosis and inflammation. Mechanistically, NEAT1 directly bound to and negatively regulated miR-301b-3p expression, whereas miR-301b-3p inhibitors abolished the inhibitory effect of NEAT1 knockdown on cell apoptosis and inflammation. As a target of miR-301b-3p, TLR4 was regulated by NEAT1 and miR-301b-3p. TLR4 overexpression alleviated NEAT1 silencing-induced inflammatory suppression. Rescue experiments demonstrated that NEAT1 promoted TLR4 expression by inhibiting miR-301b-3p. Collectively, the results of the present study suggested that NEAT1 may attenuate LPS-induced inflammation and apoptosis in HMEECs by modulating the miR-301b-3p/TLR4 axis, and may provide a new therapeutic target for the clinical treatment of AOM.

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“…Studies from our and other labs have undoubtedly shown that eCIRP is a major contributing factor causing neuroin ammation, neuronal injury and memory dysfunction in various settings [7,8,9,10,33,34].…”

Section: Discussionmentioning

confidence: 96%

“…The neurodegeneration and dysfunction is essentially caused by the deregulation of multiple complex and diverse signal transduction pathways, many of which are required for normal regulated functions, which get abnormally triggered or repressed [31,32]. Studies from our and other labs have undoubtedly shown that eCIRP is a major contributing factor causing neuroin ammation, neuronal injury and memory dysfunction in various settings [7,8,9,10,33,34].…”

Section: Discussionmentioning

confidence: 99%

Extracellular CIRP Activates the IL-6Rα/STAT3/Cdk5 Pathway in Neurons

Sharma

Jacob

Marambaud

et al. 2021

Preprint

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Extracellular cold-inducible RNA-binding protein (eCIRP) stimulates microglial inflammation causing neuronal damage during ischemic stroke and is a critical mediator of alcohol-induced cognitive impairment. However, the precise role of eCIRP in mediating neuroinflammation remains unknown. In this study, we report that eCIRP activates neurotoxic cyclin-dependent kinase-5 (Cdk5)/p25 through the induction of IL-6Rα/STAT3 pathway in neurons. Amyloid b (Aβ)-mediated neuronal stress, which is associated with Alzheimer’s disease, increased levels of eCIRP released from BV2 microglial cells. The released eCIRP levels from BV2 cells increased 3.2-fold upon stimulation with conditioned medium from Neuro-2a (N2a) cells containing Aβ compared to control N2a supernatant in a time-dependent manner. Stimulation of N2a cells and primary neurons with eCIRP upregulated the neuronal Cdk5 activator p25 expression in a dose- and time-dependent manner. eCIRP directly induced neuronal STAT3 phosphorylation and p25 increase via its novel receptor IL-6Rα. Next, we showed using surface plasmon resonance that eCIRP-derived peptide C23 inhibited the binding of eCIRP to IL-6Rα at 25 mM, with a 40-fold increase in equilibrium dissociation constant (Kd) value (from 8.08 x 10-8 M to 3.43 x 10-6 M), and completely abrogated the binding at 50 mM. Finally, C23 reversed the eCIRP-induced increase in neuronal STAT3 phosphorylation and p25 levels. In conclusion, the current study demonstrates that upregulation of neuronal IL-6Rα/STAT3/Cdk5 pathway is a key mechanism of eCIRP’s role in neuroinflammation and that C23 as a potent inhibitor of this pathway, has translational potential in neurodegenerative pathologies controlled by eCIRP.

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Cold‐inducible RNA‐binding protein contributes to intracerebral hemorrhage‐induced brain injury via TLR4 signaling

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 15 publications

References 21 publications

Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1β/CXCL1 Signaling

Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1β/CXCL1 Signaling

Long non‑coding RNA NEAT1 contributes to lipopolysaccharide‑induced inflammation and apoptosis of human middle ear epithelial cells via regulating the miR‑301b‑3p/TLR4 axis

Extracellular CIRP Activates the IL-6Rα/STAT3/Cdk5 Pathway in Neurons

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Cold‐inducible RNA‐binding protein contributes to intracerebral hemorrhage‐induced brain injury via TLR4 signaling

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 15 publications

References 21 publications

Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1β/CXCL1 Signaling

Emodin Alleviates Severe Acute Pancreatitis-Associated Acute Lung Injury by Inhibiting the Cold-Inducible RNA-Binding Protein (CIRP)-Mediated Activation of the NLRP3/IL-1β/CXCL1 Signaling

Long non‑coding RNA NEAT1 contributes to lipopolysaccharide‑induced inflammation and apoptosis of human middle ear epithelial cells via regulating the miR‑301b‑3p/TLR4 axis

Extracellular CIRP&nbsp;Activates the IL-6Rα/STAT3/Cdk5 Pathway&nbsp;in Neurons

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Extracellular CIRP Activates the IL-6Rα/STAT3/Cdk5 Pathway in Neurons