MiR‐181b inhibits P38/<scp>JNK</scp> signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid‐induced epilepsy via targeting <scp>TLR</scp>4

Wang, Li; Song, Ling; Chen, Xiaoyi; Ma, Yanli; Suo, Junfang; Shi, Jinghe; Chen, Guohong

doi:10.1111/cns.12991

Cited by 61 publications

(32 citation statements)

References 46 publications

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“…45 Recently, several studies indicated that inhibition of TLR4 by siRNA or inhibitors increased the protein expression of Bcl-2 in vivo. 46,47 In agreement with the results of Liu et al, 45 we detected increased expression of Bcl-2 rather than decreased expression of cleaved caspase-8 in TDI-treated TLR4 −/− mice compared with WT mice, indicating that the intrinsic apoptotic pathway was mainly implicated in TLR4induced neutrophil apoptosis. In addition, we also observed that either ABT-199 or ABT-737 could effectively promote neutrophil apoptosis in TDI-exposed TLR4-deficient mice, thereby markedly alleviating TDI-induced airway inflammation.…”

Section: Discussionsupporting

confidence: 91%

Toll-like Receptor 4 Deficiency Aggravates Airway Hyperresponsiveness and Inflammation by Impairing Neutrophil Apoptosis in a Toluene Diisocyanate-Induced Murine Asthma Model

Chen

Deng

et al. 2020

Allergy Asthma Immunol Res

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Accumulating evidence has suggested that toll-like receptor 4 (TLR4) is critically involved in the pathogenesis of asthma. The aim of this study was to investigate the role of TLR4 in toluene diisocyanate (TDI)-induced allergic airway inflammation. Methods: TLR4 −/− and wild-type (WT) C57BL/10J mice were sensitized and challenged with TDI to generate a TDI-induced asthma model. B-cell lymphoma 2 (Bcl-2) inhibitors, ABT-199 (4 mg/kg) and ABT-737 (4 mg/kg), were intranasally given to TDI-exposed TLR4 −/− mice after each challenge. Results: TDI exposure led to increased airway hyperresponsiveness (AHR), granulocyte flux, bronchial epithelial shedding and extensive submucosal collagen deposition, which were unexpectedly aggravated by TLR4 deficiency. Following TDI challenge, TLR4 −/− mice exhibited down-regulated interleukin-17A and increased colony-stimulating factor 3 in bronchoalveolar lavage fluid (BALF), while WT mice did not. In addition, TLR4 deficiency robustly suppressed the expression of NOD-like receptor family pyrin domain containing 3 and NLR family CARD domain containing 4, decreased caspase-1 activity in TDI-exposed mice, but had no effect on the level of high mobility group box 1 in BALF. Flow cytometry revealed that TDI hampered both neutrophil and eosinophil apoptosis, of which neutrophil apoptosis was further inhibited in TDI-exposed TLR4 −/− mice, with marked up-regulation of Bcl-2. Moreover, inhibition of Bcl-2 with either ABT-199 or ABT-737 significantly alleviated neutrophil recruitment by promoting apoptosis. Conclusions: These data indicated that TLR4 deficiency promoted neutrophil infiltration by impairing its apoptosis via up-regulation of Bcl-2, thereby resulting in deteriorated AHR and

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Section: Discussionsupporting

confidence: 91%

Toll-like Receptor 4 Deficiency Aggravates Airway Hyperresponsiveness and Inflammation by Impairing Neutrophil Apoptosis in a Toluene Diisocyanate-Induced Murine Asthma Model

Chen

Deng

et al. 2020

Allergy Asthma Immunol Res

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“…In microglia, p38 MAPK signaling has been shown to be essential for the production of proinflammatory factors such as TNF-a and IL-1b (23) and to be critical for LPS-induced neuron degeneration (24). Evidence from recent studies indicates that inhibition of p38 attenuates autophagy and apoptosis through JNK pathway (25,26). Moreover, puncta formation and recruitment of p62 were regulated by p38, and, collectively, p38 transcriptionally up-regulates p62 expression levels, resulting in the formation of amikacin liposome inhalation suspension, which are substrates for autophagy (27).…”

mentioning

confidence: 99%

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

Yao

Zhu

et al. 2019

FASEB j.

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Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and nonmotor symptoms due to the selective loss of midbrain dopaminergic neurons. The evidence for a chronic inflammatory reaction mediated by microglial cells in the brain is particularly strong in PD. In our previous study, we have shown that brain‐specific microRNA‐124 (miR‐124) is significantly down‐regulated in the 1‐methy1‐4‐pheny1‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced mouse model of PD and that it can also inhibit neuroinflammation during the development of PD. However, further investigation is required to understand whether the abnormal expression of miR‐124 regulates microglial activation. In this study, we found that the expression of sequestosome 1 (p62) and phospho‐p38 mitogen‐activated protein kinases (p‐p38) showed a significant increase in LPS‐treated immortalized murine microglial cell line BV2 cells in an MPTP‐induced mouse model of PD. Knockdown of p62 could suppress the secretion of proinflammatory cytokines and p‐p38 of microglia. Besides, inhibition of p38 suppressed the secretion of proinflammatory cytokines and promoted autophagy in BV2 cells. Moreover, our study is the first to identify a unique role of miR‐124 in mediating the microglial inflammatory response by targeting p62 and p38 in PD. In the microglial culture supernatant transfer model, the knockdown of p62 in BV2 cells prevented apoptosis and death of human neuroblastoma cell lines SH‐SY5Y (SH‐SY5Y) cells following microglia activation. In addition, the exogenous delivery of miR‐124 could suppress p62 and p‐p38 expression and could also attenuate the activation of microglia in the substantia nigra par compacta of MPTP‐treated mice. Taken together, our data suggest that miR‐124 could inhibit neuroinflammation during the development of PD by targeting p62, p38, and autophagy, indicating that miR‐124 could be a potential therapeutic target for regulating the inflammatory response in PD.—Yao, L., Zhu, Z., Wu, J., Zhang, Y., Zhang, H., Sun, X., Qian, C., Wang, B., Xie, L., Zhang, S., Lu, G. MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease. FASEB J. 33,8648–8665 (2019). http://www.fasebj.org

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“…Past studies have indicated that the manipulation of miRNAs before SE or post-SE modifies the occurrence of spontaneous seizures in experiment models. 28,35,36 Whether the manipulation of miRNAs during the chronic phase regulates epileptogenesis remains unknown. miR-135a regulates synaptic transmission and adult neurogenesis in the central nervous system (CNS) 37,38 and plays important roles in nervous system diseases.…”

Section: Mir-135amentioning

confidence: 99%

“…65 In kainic acid-induced epileptic juvenile rats, miR-181b agomirs targeting tlr4 of the hippocampus reduced seizure severity during the acute phase by attenuating autophagy and apoptosis. 35 In addition, miR-181b is known to be an anti-inflammatory miRNA that inhibits nuclear factor-κB activation and regulates the neuroinflammatory responses of astrocytes. 66,67 In the future, the roles of miR-181b in neuroinflammation should be assessed to identify possible targets for curing epilepsy.…”

Section: Mir-181bmentioning

confidence: 99%

MicroRNAs and target genes in epileptogenesis

et al. 2020

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Epilepsy is a chronic brain dysfunction. Current antiepileptic medicines cannot prevent epileptogenesis. Increasing data have shown that microRNAs (miRNAs) are selectively altered within the epileptic hippocampi of experimental models and human tissues, and these alterations affect the genes that control epileptogenesis. Furthermore, manipulation of miRNAs in animal models can modify epileptogenesis. As a result, miRNAs have been proposed as promising targets for treating epilepsy. We searched PubMed using the terms "microRNAs/miRNAs AND epilepsy", "microRNAs/miRNAs AND epileptogenesis", and "microRNAs/miRNAs AND seizure". We selected the articles in which the relationship between miRNAs and target gene(s) was validated and manipulation of miRNAs in in vivo epilepsy models modified epileptogenesis during the chronic phase via gene regulation. A total of 13 miRNAs were found in the present review. Based on the current analysis of miRNAs and their target gene(s), each miRNA has limitations as a potential epilepsy target. Importantly, miR-211 or miR-128 transgenic mice displayed seizures. These findings highlight new developments for epileptogenesis prevention. Developing novel strategies to modify epileptogenesis will be effective in curing epilepsy patients. This article provides an overview of the clinical application of miRNAs as novel targets for epilepsy.

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MiR‐181b inhibits P38/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid‐induced epilepsy via targeting TLR4

Abstract: MiR-181b could inhibit P38/JNK signaling pathway via targeting TLR4, thereby exerting protective roles in attenuating autophagy and apoptosis of KA-induced epileptic juvenile rats.

Cited by 61 publications

References 46 publications

Toll-like Receptor 4 Deficiency Aggravates Airway Hyperresponsiveness and Inflammation by Impairing Neutrophil Apoptosis in a Toluene Diisocyanate-Induced Murine Asthma Model

Toll-like Receptor 4 Deficiency Aggravates Airway Hyperresponsiveness and Inflammation by Impairing Neutrophil Apoptosis in a Toluene Diisocyanate-Induced Murine Asthma Model

MicroRNA‐124 regulates the expression of p62/p38 and promotes autophagy in the inflammatory pathogenesis of Parkinson's disease

MicroRNAs and target genes in epileptogenesis

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