Hyperbaric Oxygen Alleviates the Inflammatory Response Induced by LPS Through Inhibition of NF-κB/MAPKs-CCL2/CXCL1 Signaling Pathway in Cultured Astrocytes

Liu, Su; Lu, Chun; Liu, Ying; Zhou, Xin; Sun, Li; Gu, Qi; Shen, Guohua; A, Guo

doi:10.1007/s10753-018-0843-2

Cited by 31 publications

(31 citation statements)

References 32 publications

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“…Alternatively, the p38 inhibitor had no obvious effect on expression levels of CCL2 and CXCL1. We further demonstrated that HBOT inhibited neuroin ammation via suppression of LPS-induced MAPK (JNK and ERK)/NF-κB-CCL2/CXCL1 signaling pathways in astrocytes [11]. In this study, a TRAF6 siRNA downregulated the expression levels of CCL2, CXCL1, p-NF-κB, p-JNK, p-ERK, and p-p38 in cultured astrocytes activated by LPS.…”

Section: Traumatic Brain Injury In Rats Signi Cantly Upregulated the supporting

confidence: 50%

“…A sham operation group underwent the same surgical procedure but did not receive experimental TBI. Culture of primary cortical astrocytes Primary astrocyte cultures were prepared from the cerebral cortices of neonatal rats [11,21,22] purchased from the Experimental Animal Center of Nantong University. Bilateral cerebral cortices were isolated and transferred to ice-cold D-Hank's buffer.…”

Section: Animals and Surgerymentioning

confidence: 99%

“…We further demonstrated that in vitro administration of pro-in ammatory lipopolysaccharide (LPS) signi cantly upregulated expression levels of CCL2 and CXCL1 as well as phosphorylation (activation) of the stressassociated transcription factor nuclear factor-kappa B (NF-κB) and the mitogen-activated protein kinases (MAPKs) c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 in cultured astrocytes prepared from cerebral cortices of neonatal rats. Conversely, HBOT inhibited LPS-induced MAPK/NF-κB-CCL2/CXCL1 signaling pathways [11].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Traumatic Brain Injury In Rats Signi Cantly Upregulated the supporting

confidence: 50%

Section: Animals and Surgerymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Huang

Xia

Sun

et al. 2020

Preprint

Self Cite

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“…Primary astrocyte cultures were prepared from the cerebral cortices of neonatal rats (Gao et al, 2009;Lu et al, 2014;Liu et al, 2018) purchased from the Experimental Animal Center of Nantong University. Bilateral cerebral cortices were isolated and transferred to ice-cold D-Hank's buffer.…”

Section: Culture Of Primary Cortical Astrocytesmentioning

confidence: 99%

“…We further demonstrated that in vitro administration of pro-inflammatory lipopolysaccharide (LPS) significantly upregulated expression levels of CCL2 and CXCL1 as well as phosphorylation (activation) of the stress-associated transcription factor nuclear factor-kappa B (NF-κB) and the mitogen-activated protein kinases (MAPKs), c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), and p38 in cultured astrocytes prepared from cerebral cortices of neonatal rats. Conversely, neuroinflammation was modulated via regulation of LPS-induced MAPK/NF-κB-CCL2/CXCL1 signaling pathways (Liu et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Pathogenic Functions of Tumor Necrosis Factor Receptor-Associated Factor 6 Signaling Following Traumatic Brain Injury

Huang

Xia

Sun

et al. 2021

Front. Mol. Neurosci.

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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. 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-κB, MAPKs (ERK, JNK, and 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-κB 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. 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-ERK, p-JNK, 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. Targeting TRAF6-MAPKs/NF-κB-chemokine signaling pathways may provide a novel therapeutic approach for reducing post-TBI neuroinflammation and concomitant secondary injury.

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The neuroprotection of hyperbaric oxygen therapy against traumatic brain injury via NF-κB/MAPKs-CXCL1 signaling pathways

et al. 2021

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BackgroundIt is well known that hyperbaric oxygen (HBO) therapy achieves neuroprotective effects by suppressing or relieving neuroin ammatory responses. However, its underlying therapeutic mechanisms are not yet fully elucidated. Based on our previous studies, we further investigated whether HBO therapy exerts neuroprotective effects in vivo by regulating the NF-κB/ MAPKs-CXCL1 in ammatory pathway. MethodsA rat model of traumatic brain injury (TBI) was established by controlled cortical impact (CCI). The cellular distribution of CXCL1 and CXCR2 was observed by double immuno uorescence labeling. The neurological function of TBI rats was assessed by modi ed neurological severity scores and Morris water maze methods. TUNEL staining was performed to observe apoptosis of neuronal cells in the injured cortical area. The changes in neural function, neuronal apoptosis, and expression of CXCL1, CXCR2, NF-κB, and MAPKs (ERK and JNK) were observed in TBI rats treated with CXCR2 antagonist, ERK, JNK, and NF-κB inhibitor or HBO therapy. ResultsThe expression of CXCL1 and CXCR2 increased after TBI, and cell localization analysis revealed that CXCL1 was mainly expressed in astrocytes, while CXCR2 was mainly expressed in neurons. Increased apoptosis of cortical neurons in the injury area was also found after TBI. Reduced neuronal apoptosis with improved neurological function was observed after application of a CXCR2 antagonist. The expression of p-ERK, p-JNK and p-NF-κB increased after TBI, and application of ERK, JNK and NF-κB inhibitors decreased expression of CXCL1 and CXCR2 in rats. We further found that HBO therapy downregulated the expression of p-ERK, p-JNK, p-NF-κB, CXCL1, and CXCR2, and reduced neuronal apoptosis, improved the neurological function of TBI rats, and ultimately alleviated the secondary injury. ConclusionsCXCL1-CXCR2 mediates the interaction of activated astrocytes and neurons, exacerbating secondary injury after TBI. HBO therapy exerts neuroprotective effects by regulating the NF-κB/ MAPKs (JNK and ERK)-CXCL1 in ammatory pathway to control neuroin ammation after TBI, which provides the theoretical and experimental basis for the clinical application of HBO therapy in the treatment of TBI.

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Hyperbaric Oxygen Alleviates the Inflammatory Response Induced by LPS Through Inhibition of NF-κB/MAPKs-CCL2/CXCL1 Signaling Pathway in Cultured Astrocytes

Cited by 31 publications

References 32 publications

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

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

Pathogenic Functions of Tumor Necrosis Factor Receptor-Associated Factor 6 Signaling Following Traumatic Brain Injury

The neuroprotection of hyperbaric oxygen therapy against traumatic brain injury via NF-κB/MAPKs-CXCL1 signaling pathways

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