TRAF6-p38/JNK-ATF2 axis promotes microglial inflammatory activation

Li, Mengmeng; Zhang, Dongmei; Zhu, Xiangyang; Zhou, Yong; Zhang, Yi; Peng, Xiao; Shen, Aiguo

doi:10.1016/j.yexcr.2019.02.005

Cited by 56 publications

(40 citation statements)

References 63 publications

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“…ATF2 has previously been extensively investigated in a variety of developmental and pathological conditions [31] . A recent investigation found that ATF2 was upregulated in a mouse neuroinflammation model [13] . The promotive function of ATF2 in inflammation has also been identified in another study [13] .…”

Section: Discussionmentioning

confidence: 99%

“…A recent investigation found that ATF2 was upregulated in a mouse neuroinflammation model [13] . The promotive function of ATF2 in inflammation has also been identified in another study [13] . ATF2 decreases the expression of ATF3, leading to an inflammatory state [32] .…”

Section: Discussionmentioning

confidence: 99%

“…Bioinformatics analysis was adopted and predicted that lncRNA HIF1A-AS2 can regulate activating transcription factor 2 (ATF2). ATF2 is a member of the alkaline-leucine zipper class of proteins and is broadly expressed in a variety of tissues and involved in inflammatory responses [13] . Recent research has implicated ATF2 in the modulation of fatty diet-induced atherogenesis [14] .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of long noncoding RNA HIF1A-AS2 confers protection against atherosclerosis via ATF2 downregulation

Xing

Zhang

et al. 2020

Journal of Advanced Research

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Graphical abstract The map illustrating mechanisms associated with lncRNA HIF1A-AS2-mediated inflammation in the atherosclerosis. LncRNA HIF1A-AS2 forms a complex with USF1, which is recruited into the ATF2 promoter to elevate ATF2 expression, thus promoting the development of atherosclerotic inflammation. Meanwhile, downregulation of lncRNA HIF1A-AS2 decreases the expression of ATF2 by reducing the binding of USF1 to the ATF2 promoter regions, thereby inhibiting atherosclerotic inflammation, as reflected by decreased inflammatory factors TNF-α, IL-1β and IL-6 in serum and protein levels of adhesion molecules VCAM-1, ICAM-1, and MCP-1, as well as increased cell viability and reduced apoptosis in ox-LDL-induced inflammation in ECs, SMCs, and HCAECs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of long noncoding RNA HIF1A-AS2 confers protection against atherosclerosis via ATF2 downregulation

Xing

Zhang

et al. 2020

Journal of Advanced Research

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“…Their activation is involved in the production of inflammation mediators; as such, they are potential therapeutic targets for anti-inflammatory responses [ 7 ]. Activated MAPKs phosphorylate various substrate proteins, including proinflammatory transcription factors, such as c-Jun, c-Fos, Elk-1, activating transcription factor 2 (ATF2), and myocyte enhancer factor; thus, they positively regulate gene transcription [ 32 , 33 ]. In microglia, TLR4 signaling stimulated by LPS increases the phosphorylation of MAPKs, including JNK, p38 MAPK, and ERK, and upregulates the expression of proinflammatory cytokines, chemokines, and inflammatory responses [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Hp-s1 Ganglioside Suppresses Proinflammatory Responses by Inhibiting MyD88-Dependent NF-κB and JNK/p38 MAPK Pathways in Lipopolysaccharide-Stimulated Microglial Cells

Shih

Tsai

et al. 2020

Marine Drugs

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Hp-s1 ganglioside is isolated from the sperm of sea urchin (Hemicentrotus pulcherrimus). In addition to neuritogenic activity, the biological function of Hp-s1 in neuroinflammation is unknown. In this study, we investigated the anti-neuroinflammatory effect of Hp-s1 on lipopolysaccharide (LPS)-stimulated microglial cells. MG6 microglial cells were stimulated with LPS in the presence or absence of different Hp-s1 concentrations. The anti-inflammatory effect and underlying mechanism of Hp-s1 in LPS-activated microglia cells were assessed through a Cell Counting kit-8 assay, Western blot analysis, and immunofluorescence. We found that Hp-s1 suppressed not only the expression of inducible nitric oxide synthase and cyclooxygenase-2 but also the expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Hp-s1 inhibited the LPS-induced NF-κB signaling pathway by attenuating the phosphorylation and translocation of NF-κB p65 and by disrupting the degradation and phosphorylation of inhibitor κB-α (IκBα). Moreover, Hp-s1 inhibited the LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK). Hp-s1 also reduced the expression of myeloid differentiation factor 88 (MyD88) and TNF receptor-associated factors 6 (TRAF6), which are prerequisites for NF-κB and MAPKs activation. These findings indicated that Hp-s1 alleviated LPS-induced proinflammatory responses in microglial cells by downregulating MyD88-mediated NF-κB and JNK/p38 MAPK signaling pathways, suggesting further evaluation as a new anti-neuroinflammatory drug.

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“…Chen et al [15] found that TRAF6 was highly expressed in cortical reactive astrocytes and neurons after TBI and promoted neuronal apoptosis. Other studies have reported that TRAF6 acts as an adaptor in a number of signaling pathways that positively regulate downstream kinase cascades, such as NF-κB, JNK, and p-38, among others [16][17][18]. Based on these ndings, the present study examined if TRAF6 participates in TBI-induced neuroin ammation and associated functional de cits by regulating MAPK/NF-κB-CCL2/CXCL1 signaling pathways.…”

Section: Introductionmentioning

confidence: 87%

Pathogenic Functions of Tumor Necrosis Factor Receptor-associated Factor 6 Signaling following Traumatic Brain Injury

Huang

Xia

Sun

et al. 2020

Preprint

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Background: Neuroinflammation contributes to delayed (secondary) neurodegeneration following traumatic brain injury (TBI). Tumor necrosis factor receptor-associated factor 6 (TRAF6) signaling may promote post-TBI neuroinflammation, thereby exacerbating secondary injury. Methods: This study investigated the pathogenic functions of TRAF6 signaling following TBI in vivo and in vitro. A rat TBI model was established by air pressure contusion while lipopolysaccharide (LPS) exposure was used to induce inflammatory-like responses in cultured astrocytes. Model rats were examined for cell-specific expression of TRAF6, NF-κB, phosphorylated (p)-NF-kB, MAPKs (ERK, JNK, p38), p-MAPKs, chemokines (CCL2 and CXCL1), and chemokine receptors (CCR2 and CXCR2) by immunofluorescence, RT-qPCR, western blotting, and ELISA, for apoptosis by TUNEL staining, and spatial cognition by Morris water maze testing. These measurements were compared between TBI model rats receiving intracerebral injections of TRAF6-targeted RNAi vector (AAV9-TRAF6-RNAi), empty vector, MAPK/NF-kB inhibitors, or vehicle. Primary astrocytes were stimulated with LPS following TRAF6 siRNA or control transfection, and NF-κB, MAPKs, chemokine, and chemokine receptor expression levels evaluated by western blotting and ELISA. Results: TRAF6 was expressed mainly in astrocytes and neurons of injured cortex, peaking 3 days post-TBI. Knockdown by AAV9-TRAF6-RNAi improved spatial learning and memory, decreased TUNEL-positive cell number in injured cortex, and downregulated expression levels of p-NF-κB, p-JNK, p-ERK, p-p38, CCL2, CCR2, CXCL1, and CXCR2 post-TBI. Inhibitors of NF-κB, ERK, JNK, and p38 significantly suppressed CCL2, CCR2, CXCL1, and CXCR2 expression following TBI. Furthermore, TRAF6-siRNA inhibited LPS-induced NF-κB, ERK, JNK, p38, CCL2, and CXCL1 upregulation in cultured astrocytes. Conclusions: Targeting TRAF6-MAPK/NF-κB-chemokine signaling pathways may provide a novel therapeutic approach for reducing post-TBI neuroinflammation and concomitant secondary injury.

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TRAF6-p38/JNK-ATF2 axis promotes microglial inflammatory activation

Cited by 56 publications

References 63 publications

Inhibition of long noncoding RNA HIF1A-AS2 confers protection against atherosclerosis via ATF2 downregulation

Inhibition of long noncoding RNA HIF1A-AS2 confers protection against atherosclerosis via ATF2 downregulation

Hp-s1 Ganglioside Suppresses Proinflammatory Responses by Inhibiting MyD88-Dependent NF-κB and JNK/p38 MAPK Pathways in Lipopolysaccharide-Stimulated Microglial Cells

Pathogenic Functions of Tumor Necrosis Factor Receptor-associated Factor 6 Signaling following Traumatic Brain Injury

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