TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury

Xu, Shun; Wang, Jin; Jiang, Jianyuan; Song, Jian; Zhu, Wei; Zhang, Fan; Shao, Minghao; Xu, Haocheng; Ma, Xiaosheng; Lyu, Feizhou

doi:10.1038/s41419-020-02824-z

Cited by 120 publications

(80 citation statements)

References 61 publications

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“…Neuroinflammation plays a crucial role in the secondary phase of SCI, and is initiated following the activation of TLR4. Pyroptosis is a form of inflammatory programmed cell death, which is closely involved in neuroinflammation, and it can be regulated by TLR4 according to a recent research ( 12 ). BMSCs-derived exosomes could inhibit apoptosis and inflammation response induced by spinal cord injury and promote motor function recovery by inhibiting the TLR4/MyD88/NF-κB signaling pathway ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

“…Changes in the gut microbiota lead to neuroinflammation and intestinal damage through intestinal leakage and TLR4 activation ( 11 ). TLR4 promotes microglial apoptosis by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway after SCI ( 12 ). Following SCI, necrotic astrocytes induce high inflammatory response genes encoding TLR4 and myeloid differentiation primary response gene 88 (MyD88) ( 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Gut Microbiota Disorders Promote Inflammation and Aggravate Spinal Cord Injury Through the TLR4/MyD88 Signaling Pathway

et al. 2021

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Background: In spinal cord injury (SCI), systemic inflammation and the death of nerve cells in the spinal cord are life threatening. The connection between gut microbiota and signaling pathways has been a hot research topic in recent years. The Toll-like receptor 4/Myeloid differentiation factor 88 (TLR4/MyD88) signaling pathway is closely related to the inflammatory response. This study explored whether the gut microbiota imbalance could affect the TLR4/MyD88 signaling pathway to regulate SCI to provide a new basis for SCI research and treatment.Methods: An SCI model was constructed to study the influence on the injury of gut microbiota. 16S amplicon sequencing was used to identify the diversity and abundance of gut microbes. Fecal microbiota transplantation was performed in mice with SCI. ELISA was used to detect the serum levels of pro-inflammatory and anti-inflammatory factors in mice. Hematoxylin and eosin staining was used to observe SCI in mice. Immunofluorescence was used to detect the rates of loss glial fibrillary acidic protein (GFAP), neuronal nuclear protein (NeuN), and ionized calcium-binding adapter molecule 1 (IBA1) in the spinal cord as indicators of apoptosis. The expression of the TLR4/MyD88 signaling pathway was detected by qRT-PCR and western blotting.Results: Significant differences were observed in the gut microbiota of SCI mice and normal mice. The gut microbiota of SCI mice was imbalanced. The levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 in SCI mice were increased, as was the level of the toxic induced nitric oxide synthase. The levels of anti-inflammatory factors IL-4, transforming growth factor-β, and IL-10 were decreased, as was the level of arginase-1. The apoptosis rates of GFAP, NeuN, and IBA1 were increased. The TLR4/MyD88 signaling pathway was activated. In the SCI group, inflammation increased after fecal transplantation, apoptosis of GFAP, NeuN, and IBA1 increased, and SCI was more serious.Conclusion: The TLR4/MyD88 signaling pathway promotes the death of nerve cells by inducing inflammation. Gut microbiota dysregulation can lead to aggravated SCI by activating the TLR4/MyD88 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gut Microbiota Disorders Promote Inflammation and Aggravate Spinal Cord Injury Through the TLR4/MyD88 Signaling Pathway

et al. 2021

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“…The first 20 results of the (adjusted P value based) KEGG pathway enrichment analysis of 189 potential therapeutic targets of BYHWD against SCI have been presented, and we screened the enriched pathways again to find possible relevant pathways for SCI. By searching the relevant literature, we screened a total of 15 pathways with strong relevance, as follows: AGE-RAGE signaling pathway in diabetic complications (hsa04933) [ 43 ], TNF signaling pathway (hsa04668), Apoptosis (hsa04210) [ 44 ], Pathways of neurodegeneration-multiple diseases (hsa05022), Toll-like receptor signaling pathway (hsa04620) [ 45 ], PI3K-Akt signaling pathway (hsa04151) [ 46 ], HIF-1 signaling pathway (hsa04066) [ 47 ], MAPK signaling pathway (hsa04010) [ 48 ], NF-kappa B signaling pathway (hsa04064) [ 49 ], EGFR tyrosine kinase inhibitor resistance (hsa01521) [ 50 ], JAK-STAT signaling pathway (hsa04630) [ 51 ], Wnt signaling pathway (hsa04310) [ 43 ], AMPK signaling pathway (hsa04152) [ 44 ], and mTOR signaling pathway (hsa04150) [ 46 ]. The above pathways and hub genes are not in a disconnected relationship; rather, many hub genes are important components of some of the pathways.…”

Section: Discussionmentioning

confidence: 99%

Deciphering Pharmacological Mechanism of Buyang Huanwu Decoction for Spinal Cord Injury by Network Pharmacology Approach

Xiong

Yang

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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Objective. The purpose of this study was to investigate the mechanism of action of the Chinese herbal formula Buyang Huanwu Decoction (BYHWD), which is commonly used to treat nerve injuries, in the treatment of spinal cord injury (SCI) using a network pharmacology method. Methods. BYHWD-related targets were obtained by mining the TCMSP and BATMAN-TCM databases, and SCI-related targets were obtained by mining the DisGeNET, TTD, CTD, GeneCards, and MalaCards databases. The overlapping targets of the abovementioned targets may be potential therapeutic targets for BYHWD anti-SCI. Subsequently, we performed protein-protein interaction (PPI) analysis, screened the hub genes using Cytoscape software, performed Gene Ontology (GO) annotation and KEGG pathway enrichment analysis, and finally achieved molecular docking between the hub proteins and key active compounds. Results. The 189 potential therapeutic targets for BYHWD anti-SCI were overlapping targets of 744 BYHWD-related targets and 923 SCI-related targets. The top 10 genes obtained subsequently included AKT1, IL6, MAPK1, TNF, TP53, VEGFA, CASP3, ALB, MAPK8, and JUN. Fifteen signaling pathways were also screened out after enrichment analysis and literature search. The results of molecular docking of key active compounds and hub target proteins showed a good binding affinity for both. Conclusion. This study shows that BYHWD anti-SCI is characterized by a multicomponent, multitarget, and multipathway synergy and provides new insights to explore the specific mechanisms of BYHWD against SCI.

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“…Pyroptosis is a type of programmed cell death involved in neuroinflammation (Dai et al, 2019). And it is proved that inhibiting microglial pyroptosis can promote motor function recovery following SCI (Xu S. et al, 2020). F630028O10Rik levels are higher in the peripheral blood from SCI patients compared with normal people.…”

Section: Spinal Cord Injurymentioning

confidence: 99%

“…Subsequently, increased Colla1 can enhance microglial pyroptosis through the activation of phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway. Increased F630028O10Rik expression can indicate worse functional recovery after SCI (Xu S. et al, 2020). Smad ubiquitination regulatory factor 1 (Smurf1) is a downstream target of miR-27a and its expression can be attenuated by miR-27a.…”

Section: Spinal Cord Injurymentioning

confidence: 99%

Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

Chen

Lai

Wang

et al. 2021

Front. Mol. Neurosci.

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Microglia and astrocytes maintain tissue homeostasis in the nervous system. Both microglia and astrocytes have pro-inflammatory phenotype and anti-inflammatory phenotype. Activated microglia and activated astrocytes can contribute to several neurological diseases. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), two groups of non-coding RNAs (ncRNAs), can function as competing endogenous RNAs (ceRNAs) to impair the microRNA (miRNA) inhibition on targeted messenger RNAs (mRNAs). LncRNAs and circRNAs are involved in various neurological disorders. In this review, we summarized that lncRNAs and circRNAs participate in microglia dysfunction, astrocyte dysfunction, neuron damage, and inflammation. Thereby, lncRNAs and circRNAs can positively or negatively regulate neurological diseases, including spinal cord injury (SCI), traumatic brain injury (TBI), ischemia-reperfusion injury (IRI), stroke, neuropathic pain, epilepsy, Parkinson’s disease (PD), multiple sclerosis (MS), and Alzheimer’s disease (AD). Besides, we also found a lncRNA/circRNA-miRNA-mRNA regulatory network in microglia and astrocyte mediated neurological diseases. Through this review, we hope to cast light on the regulatory mechanisms of lncRNAs and circRNAs in microglia and astrocyte mediated neurological diseases and provide new insights for neurological disease treatment.

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TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury

Cited by 120 publications

References 61 publications

Gut Microbiota Disorders Promote Inflammation and Aggravate Spinal Cord Injury Through the TLR4/MyD88 Signaling Pathway

Gut Microbiota Disorders Promote Inflammation and Aggravate Spinal Cord Injury Through the TLR4/MyD88 Signaling Pathway

Deciphering Pharmacological Mechanism of Buyang Huanwu Decoction for Spinal Cord Injury by Network Pharmacology Approach

Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

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