LncRNA AK148321 alleviates neuroinflammation in LPS-stimulated BV2 microglial cell through regulating microRNA-1199-5p/HSPA5 axis

Gao, Shan; Cheng, Qiaochu; Hu, Yuwen; Tan, Zizhu; Chen, Li; Liu, Siwei; Kang, Qianyan; Wei, Ting

doi:10.1016/j.lfs.2020.118863

Cited by 21 publications

(14 citation statements)

References 28 publications

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“…Comparison of HC1 from the AD cohort compared to controls revealed several immune genes associated with endoplasmic reticulum stress and the unfolded protein response which were highly upregulated in AD brain compared to control such as HSPA5 (FC = 3.11, q =0.056), and EIF2AK3 (FC = 0.70, q =0.083; Figure 8A) (O’Connor et al, 2008; Correani et al, 2017; Ghemrawi and Khair, 2020; Gao et al, 2021). EIF2AK3, also known as PERK, is activated by virus (O’Connor et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Transcriptomically unique endolysosomal and homeostatic microglia populations in Alzheimer’s disease and aged human brain

Prater

Green

Smith

et al. 2021

Preprint

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Microglia-mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer's Disease (AD). Microglia demonstrate heterogeneous states in health and disease, with proposed beneficial, harmful, and disease specific subtypes. Defining the spectrum of microglia phenotypes is an important step in rational design of neuroinflammation modulating therapies. To facilitate improved phenotype resolution and group comparisons based on disease state we performed single-nucleus RNA-seq on more than 120,000 microglia nuclei from AD and control dorsolateral prefrontal cortex. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles. We detected several previously unrecognized microglia populations in human AD brain, including three internalization and trafficking subtypes that were heterogeneous in their metabolic and inflammatory signatures. One of these endolysosomal subtypes is larger in AD individuals and was uniquely enriched for genes involved in nucleic acid detection and activation of interferon signaling. This inflammatory endolysosomal cluster also differentially regulated expression of genes associated with AD risk by genome wide association studies. We also identified a cluster of microglia with upregulated cell cycle and DNA repair genes that is proportionately larger in control individuals. Within cluster comparisons demonstrate that in AD brain, homeostatic microglia subpopulations upregulate inflammatory gene expression. These results highlight the heterogenous nature of the microglia response to AD pathology and will inform efforts to target specific subtypes of microglia in the development of novel AD therapies.

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Section: Resultsmentioning

confidence: 99%

Transcriptomically unique endolysosomal and homeostatic microglia populations in Alzheimer’s disease and aged human brain

Prater

Green

Smith

et al. 2021

Preprint

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“…These results indicate that HSPA5 was bene cial for cell survival. HSPA5 has been shown to regulate the immune response, autophagy, and apoptosis in controlling cell viability [42][43][44]. Then we tried to explore whether HSPA5 protects cells by modulating ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

HSPA5 Repressed Ferroptosis to Promote Colorectal Cancer Development by Maintaining GPX4 Stability

Wang

Liu

et al. 2021

Preprint

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Background:Colorectal cancer (CRC) is one of the most malignant cancers and its pathological mechanism is largely unknown.Unfolded protein response and ferroptosis are both critical factors involved in CRC development. However, their relationship in CRC remains to be explored. Methods:In this study, erastin was used to induce ferroptosis in CRC cells. Cell viability and apoptosis were assessed by CCK-8 and colony formation assayand annexin V/propidium iodide staining, respectively. Ferroptosis was confirmed by the detection of glutathione, malondialdehyde, and lipid reactive oxygen species. Unfolded protein response-related proteins and GPX4 protein were analyzed by western blotting. The CRC datasetswere analyzed using the R software, GEPIA2 and TIMER2.0. Results:The results indicated that GPX4 was decreased when treated with the ferroptosis inducer erastin. As an intrinsic protective pathway, the unfolded protein response was activated and HSPA5 was increasedduring ferroptosis. HSPA5 was found to attenuateerastin-induced GPX4 decrease, repress ferroptosis, and promote CRC cell growth both in vitro and in vivo. Mechanistically, HSPA5 bounddirectly to GPX4 andthe interaction between HSPA5 and GPX4increased when treated with erastinfor a short time period. Although the HSPA5-GPX4 interaction failed to completely reverse erastin-induced GPX4 decrease, HSPA5 slowed down GPX4 degradation process and gave CRC cells more time to adjust to erastin toxicity. Additionally, HSPA5 was demonstrated to play a diagnostic role and correlated to immune microenvironment in CRC patients.Conclusion:Our study demonstrates that increased HSPA5 was an intrinsic protective strategy to resist ferroptosis. Specifically, HSPA5 restrained ferroptosis to promote colorectal cancer development by maintaining GPX4 stability. Our study provides potential diagnostic and therapeutic targets for patients with CRC.

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“…After 48 h, the cells were isolated for subsequent experiments. The lipopolysaccharide (LPS) powder was dissolved in mother liquor at a concentration of 1 mg/ml with phosphate-buffered saline (PBS), after which the cells were seeded into 12-well plates (20 × 10 4 cells/well) containing LPS (the final solubility was 1μg/ml) ( 17 ) for incubation at 37°C with 5% CO 2 . After 24 h, the cells were isolated for subsequent experimentation.…”

Section: Methodsmentioning

confidence: 99%

miR-124-3p Inhibits Microglial Secondary Inflammation After Basal Ganglia Hemorrhage by Targeting TRAF6 and Repressing the Activation of NLRP3 Inflammasome

Fang

Hong

2021

Front. Neurol.

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Objectives: Intracerebral hemorrhage (ICH) represents a serious central nervous system emergency with high morbidity and mortality, and the basal ganglia is the most commonly affected brain region. Differentially expressed microRNAs (miRs) have recently been highlighted to serve as potential diagnostic biomarkers and therapeutic targets for ICH. This study investigated the mechanism of miR-124-3p in microglial secondary inflammation after ICH.Methods: In this study, 48 patients with primary basal ganglia ICH and 48 healthy volunteers were selected and venous blood was collected from all patients on the second morning of admission (within 24 h of stroke onset). The expression of miR-124-3p in serum was detected by RT-qPCR. Three months after ICH, the patients were assessed by modified Rankin Scale (mRS), and the correlation between miR-124-3p expression and mRS score was analyzed by Pearson. The inflammatory response of microglia was induced by lipopolysaccharide (LPS) to establish the cell model of microglial inflammation. miR-124-3p expression patterns were detected in the serum of ICH patients and healthy volunteers, normal microglia, and LPS-induced microglia. The miR-124-3p mimic was transfected into LPS-induced microglia, followed by measurement of the inflammatory factors, apoptosis rate, and cell viability. The target gene of miR-124-3p was predicted and verified. The expression patterns of tumor necrosis factor receptor-associated factor 6 (TRAF6) were detected. pcDNA3.1 and pcDNA3.1-TRAF6 were transfected into LPS-induced HMC3 cells, and nucleotide-binding oligomerization domain-like receptor (NLR) pyrin domain-containing 3 (NLRP3) expression patterns were determined. Lastly, the effects of TRAF6 overexpression on apoptosis, cell viability, and inflammation in HMC3 cells were measured.Results: miR-124-3p was downregulated in the serum of basal ganglia ICH patients and LPS-induced microglia, and miR-124-3p expression was negatively correlated with mRS. Overexpression of miR-124-3p reduced the inflammatory factors and apoptosis rate and promoted cell activity in LPS-induced microglia. miR-124-3p was found to target TRAF6. Overexpression of TRAF6 enhanced the expression of NLRP3 inflammasome, inflammatory factors and apoptosis rate, and reduced cell viability.Conclusion: Our findings indicate that miR-124-3p repressed the activation of NLRP3 inflammasome by targeting TRAF6, thus inhibiting microglial secondary inflammation after ICH in basal ganglia.

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LncRNA AK148321 alleviates neuroinflammation in LPS-stimulated BV2 microglial cell through regulating microRNA-1199-5p/HSPA5 axis

Cited by 21 publications

References 28 publications

Transcriptomically unique endolysosomal and homeostatic microglia populations in Alzheimer’s disease and aged human brain

Transcriptomically unique endolysosomal and homeostatic microglia populations in Alzheimer’s disease and aged human brain

HSPA5 Repressed Ferroptosis to Promote Colorectal Cancer Development by Maintaining GPX4 Stability

miR-124-3p Inhibits Microglial Secondary Inflammation After Basal Ganglia Hemorrhage by Targeting TRAF6 and Repressing the Activation of NLRP3 Inflammasome

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