Regnase-1 in microglia negatively regulates high mobility group box 1-mediated inflammation and neuronal injury

Liu, Xiaoxi; Wang, Chen; Huang, Shaofei; Chen, Qiong; Y, Hu; Zhou, Liang; Gu, Yong

doi:10.1038/srep24073

Cited by 25 publications

(23 citation statements)

References 54 publications

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“…41 Extracellular high mobility group box 1 (HMGB-1) increases the expression of Regnase-1 in microglia, whereas Regnase-1 negatively regulates HMGB-1mediated neuroinflammation and neuronal toxicity. 42 Interestingly, several chemical treatments, such as MG-132, SAHA, silica, cholesterol and fish oil, stimulate the expression of Regnase-1. The proteasome inhibitor MG-132 induces the de novo mRNA synthesis of Regnase-1 through mechanisms that are independent of protein-degradation and dependent on ERK 1/2 and p38 kinase activation.…”

Section: Rapidly Induced Expression Of Regnase-1 After Challengesmentioning

confidence: 99%

Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses

et al. 2017

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RNA-binding proteins (RBPs) are central players in post-transcriptional regulation and immune homeostasis. The ribonuclease and RBP Regnase-1 exerts critical roles in both immune cells and non-immune cells. Its expression is rapidly induced under diverse conditions including microbial infections, treatment with inflammatory cytokines and chemical or mechanical stimulation. Regnase-1 activation is transient and is subject to negative feedback mechanisms including proteasome-mediated degradation or mucosa-associated lymphoid tissue 1 (MALT1) mediated cleavage. The major function of Regnase-1 is promoting mRNA decay via its ribonuclease activity by specifically targeting a subset of genes in different cell types. In monocytes, Regnase-1 downregulates IL-6 and IL-12B mRNAs, thus mitigating inflammation, whereas in T cells, it restricts T-cell activation by targeting c-Rel, Ox40 and Il-2 transcripts. In cancer cells, Regnase-1 promotes apoptosis by inhibiting anti-apoptotic genes including Bcl2L1, Bcl2A1, RelB and Bcl3. Together with up-frameshift protein-1 (UPF1), Regnase-1 specifically cleaves mRNAs that are active during translation by recognizing a stem-loop (SL) structure within the 3'UTRs of these genes in endoplasmic reticulum-bound ribosomes. Through this mechanism, Regnase-1 rapidly shapes mRNA profiles and associated protein expression, restricts inflammation and maintains immune homeostasis. Dysregulation of Regnase-1 has been described in a multitude of pathological states including autoimmune diseases, cancer and cardiovascular diseases. Here, we provide a comprehensive update on the function, regulation and molecular mechanisms of Regnase-1, and we propose that Regnase-1 may function as a master rapid response gene for cellular adaption triggered by microenvironmental changes.

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Section: Rapidly Induced Expression Of Regnase-1 After Challengesmentioning

confidence: 99%

Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses

et al. 2017

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“…Microglia migrate every now and then due to lacking of synaptic linkage, and they secret numerous neurotrophins or neurotoxins to support neuronal function and survival or to induce neuronal injury [58][59][60][61]. Activating microglia results in the release of pro-inflammatory mediators, including TNF-α, IL-1β and NO and these pro-inflammation mediators are the essential elements at the onset and process of neurodegenerative diseases [62][63][64][65].…”

Section: Discussionmentioning

confidence: 99%

Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

et al. 2017

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It has been reported that activation of NF-κB is involved in excitotoxicity; however, it is not fully understood how NF-κB contributes to excitotoxicity. The aim of this study is to investigate if NF-κB contributes to quinolinic acid (QA)-mediated excitotoxicity through activation of microglia. In the cultured primary cortical neurons and microglia BV-2 cells, the effects of QA on cell survival, NF-κB expression and cytokines production were investigated. The effects of BV-2-conditioned medium (BCM) on primary cortical neurons were examined. The effects of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, and minocycline (MC), an inhibitor of microglia activation, on QA-induced excitotoxicity were assessed. QA-induced NF-κB activation and TNF-α secretion, and the roles of TNF-α in excitotoxicity were studied. QA at the concentration below 1 mM had no apparent toxic effects on cultured primary neurons or BV-2 cells. However, addition of QA-primed BCM to primary neurons did aggravate QA-induced excitotoxicity. The exacerbation of QA-induced excitotoxicity by BCM was partially ameliorated by inhibiting NF-κB and microglia activation. QA induced activation of NF-κB and upregulation of TNF-α in BV-2 cells. Addition of recombinant TNF-α mimicked QA-induced excitotoxic effects on neurons, and neutralizing TNF-α with specific antibodies partially abolished exacerbation of QA-induced excitotoxicity by BCM. These studies suggested that QA activated microglia and upregulated TNF-α through NF-κB pathway in microglia. The microglia-mediated inflammatory pathway contributed, at least in part, to QA-induced excitotoxicity.

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“…MCPIP1 plays an important role in inflammatory diseases, such as pneumoconiosis 16 , neuronal injury 50 , and I/R injury 1 . MCPIP1 expression is rapidly increased in HUVECs after I/R, whereas most functional changes occur several hours after reperfusion; therefore, the downstream pathway is of interest.…”

Section: Discussionmentioning

confidence: 99%

MCPIP1-induced autophagy mediates ischemia/reperfusion injury in endothelial cells via HMGB1 and CaSR

Xie

Zhu

Chen

et al. 2018

Sci Rep

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Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) plays a important role in ischemia/ reperfusion (I/R) injury. Autophagy is involved in activating endothelial cells in response to I/R. However, researchers have not clearly determined whether MCPIP1 mediates I/R injury in endothelial cells via autophagy, and its downstream mechanism remains unclear. Western blotting analyses and immunocytochemistry were applied to detect protein levels were detected in HUVECs. An in vitro scratch assay was used to detect cell migration. Cells were transfected with siRNAs to knockdown MCPIP1 and high mobility group box 1 (HMGB1) expression. The pharmacological activator of autophagy rapamycin and the specific calcium-sensing receptor (CaSR) inhibitor NPS-2143 were used to confirm the roles of autophagy and CaSR in I/R injury. I/R induced HMGB1 and CaSR expression, which subsequently upreguated the migration and apoptosis of HUVECs and coincided with the increase of autophagy. HMGB1 was involved in cell migration, whereas CaSR specifically participated in I/R-induced HUVEC apoptosis. Based on these findings, I/R-induced MCPIP1 expression regulates the migration and apoptosis of HUVECs via HMGB1 and CaSR, respectively, suggesting a new therapeutic targetof I/R injury.Vascular endothelial cell dysfunction plays an crucial role in ischemia/reperfusion (I/R) injury, a common aspect of cardiovascular disease that is characterized by the over-production of inflammatory factors, such as cytokines and chemokines 1,2 . Various biological events, such as autophagy, endoplasmic reticulum stress (ERS) and ubiquitination, are involved in endothelial cell dysfunction. Autophagy plays an important role in the ability of cells to adapt to changing environmental conditions and in cellular remodeling during angiogenesis [3][4][5][6] . However, the mechanisms underlying I/R-induced endothelial cell dysfunction that are associated with autophagy remain poorly understood.Based on accumulating evidence, monocyte chemotactic protein-1 (MCP-1) and its downstream molecule MCP-1-induced protein 1 (MCPIP1) facilitate vascular inflammation and endothelial dysfunction in response to I/R 1, [7][8][9][10] . For example, MCPIP1 has been shown to induce angiogenesis during placental vasculogenesis, which in turn leads to vascular remodeling [11][12][13] . Interestingly, recent studies have linked MCP-1/MCPIP1 with autophagy under different conditions that induce cell activation and apoptosis. For instance, MCP-1 and MCPIP1 contribute to cardiomyoblast death in patients with heart failure and are associated with autophagy resulting from ERS 14 . Moreover, MCPIP1-induced autophagy is required for angiogenesis in patients with angiogenesis-related cardiovascular diseases 15 . On the other hand, MCPIP1/p53 expression is induced after SiO2 exposure and promotes macrophage activation and apoptosis, suggesting the presence of a general link between the MCPIP1 signaling pathway and autophagy in different diseases 16,17 .

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Regnase-1 in microglia negatively regulates high mobility group box 1-mediated inflammation and neuronal injury

Cited by 25 publications

References 54 publications

Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses

Regnase-1, a rapid response ribonuclease regulating inflammation and stress responses

Microglia activation contributes to quinolinic acid-induced neuronal excitotoxicity through TNF-α

MCPIP1-induced autophagy mediates ischemia/reperfusion injury in endothelial cells via HMGB1 and CaSR

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