Roles of Pannexin-1 Channels in Inflammatory Response through the TLRs/NF-Kappa B Signaling Pathway Following Experimental Subarachnoid Hemorrhage in Rats

Wu, Lingyun; Ye, Zhen-Nan; Zhou, Chenhui; Chun-xi, Wang; Xie, Guang-bin; Zhang, Xiangsheng; Gao, Yongyue; Zhang, Zihuan; Zhou, Meng-Liang; Zhuang, Zong; Liu, Jingpeng; Hang, Chun-Hua; Shi, Jinjie

doi:10.3389/fnmol.2017.00175

Cited by 49 publications

(37 citation statements)

References 46 publications

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“…While Panx1 is a direct target of NFκβ activation, we further demonstrate that Panx1 signaling can enhance NFκβ activation. This is in keeping with studies by Wu et al that pointed to a role of Panx1 in the control of NFκβ activation (Wu et al, 2017). Our data highlight that TNF induces an increase in P-p65 activation, that is significantly reduced when Panx1 expression is knocked down by siRNA and when the channel is blocked in the presence of the PxIL2P peptide.…”

Section: Discussionsupporting

confidence: 92%

“…ATP release through Panx1 channels has been shown to be a strong signal for the recruitment of inflammatory cells in response to apoptosis (Chekeni et al, 2010) and activation of the NLR3P inflammasome (Albalawi et al, 2017; Lappas, 2014; Wu et al, 2017). However, the precise Panx1-mediated mechanisms controlling inflammation have never been fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

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Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Yang

DeLalio

Best

et al. 2019

Preprint

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25inflammation, endothelial cell, smooth muscle cell 4 to prolonged tumor necrosis factor alpha (TNF) treatment, Yang et al. found that the Panx1 5 channel is targeted to the plasma membrane, where it facilitates an increase in intracellular 6 calcium to control the production and release of cytokines including IL-1β. 7 8 GRAPHICAL ABSTRACT 9 10 Graphical Abstract: The inflammatory process in endothelial cells is controlled by Ca 2+ entry through Pannexin 1 membrane channels. 3 Abstract 1The proinflammatory cytokine IL-1β is a significant risk factor in cardiovascular disease 2 that can be targeted to reduce major cardiovascular events. IL-1β expression and release 3 are tightly controlled by changes in intracellular Ca 2+ . In addition, purinergic signaling 4 through ATP release has also been reported to promote IL-1β production. Despite this, 5 the mechanisms that control IL-1β synthesis and expression have not been identified. 6The pannexin 1 (Panx1) channel has canonically been implicated in ATP release, 7 especially during inflammation. However, resolution of purinergic signaling occurs quickly 8 due to blood flow and the presence of ectonucleotidases. We examined Panx1 in human 9 endothelial cells following treatment with the pro-inflammatory cytokine tumor necrosis 10 alpha (TNF). In response to long-term TNF treatment, we identified a dramatic increase 11 in Panx1 protein expression at the plasma membrane. Analysis by whole transcriptome 12 sequencing (RNA-seq), qPCR, and treatment with specific kinase inhibitors, revealed that 13 TNF signaling induced NFκβ-associated Panx1 transcription. Genetic inhibition of Panx1 14 reduced the expression and secretion of IL-1β. We initially hypothesized that increased 15Panx1-mediated ATP release acted in a paracrine fashion to control cytokine expression. 16However, our data demonstrate that IL1-β expression was not altered after direct ATP 17 stimulation, following degradation of ATP by apyrase, or after pharmacological blockade 18 of P2 receptors. These data suggest that non-purinergic pathways, involving Panx1, 19 control IL-1β production. Because Panx1 forms a large pore channel, we hypothesized it 20 may act to passively diffuse Ca 2+ into the cell upon opening to regulate IL-1β. High-21 throughput flow cytometric analysis demonstrated that TNF treatments lead to elevated 22 intracellular Ca 2+ . Genetic or pharmacological inhibition of Panx1 reduced TNF-23 associated increases in intracellular Ca 2+ , and IL-1β transcription. Furthermore, we found 24 that the Ca 2+ -sensitive NFκβ-p65 protein failed to localize to the nucleus after genetic or 25 pharmacological block of Panx1. Taken together, our study provides the first evidence 26 that intracellular Ca 2+ regulation via the Panx1 channel induces a feed-forward effect on 27NFκβ to regulate IL-1β synthesis and release in endothelium during inflammation. 28 4 (Tumor Necrosis Factor)-Triggered Smooth Muscle Cell Inflammation and Attenuates

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Yang

DeLalio

Best

et al. 2019

Preprint

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“…Due to the importance of the LPS/TLR4/NF-kB pathway in the anti-inflammatory immune response, a number of studies have focused on its underlying mechanism. At present, research on TLR/NF-κB has mainly focused on the identification of TLR structure, the regulation mechanism of NF-κB activation and the nature of TLR-oriented anti-infective drugs (30,31). The present study focused on the regulatory mechanism of NF-κB activation and observed that this involved the generation of cellular ROS.…”

Section: Discussionmentioning

confidence: 73%

Inflammatory stimuli promote oxidative stress in pancreatic acinar cells via Toll-like receptor 4/nuclear factor-κB pathway

Pan

Wang

et al. 2018

Int J Mol Med

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The Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway is vital to the pathogenesis of acute pancreatitis (AP). The aim of the present study was to identify the mechanism of the activation of the TLR4/NF-κB signaling pathway in the viability of primary pancreatic cells. The cells were stimulated with lipopolysaccharide (LPS) for the activation of NF-κB signaling. Next, the reactive oxygen species (ROS) level was evaluated by detecting the concentration of malondialdehyde and glutathione peroxidase. cell viability was measured by cell counting Kit-8 and MTT assays, while the percentage of apoptosis was detected by flow cytometry. Quantitative polymerase chain reaction was used to detect TLR4, B-cell lymphoma 2 (Bcl2), Bcl2-associated X protein (Bax) and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) expression levels. Western blot assay was also conducted to detect TLR4 protein expression, while the activity of NF-κB signaling was measured by determining the p65 and phosphorylated p65 protein levels. In addition, the effect of TLR4 overexpression or treatment with TLR4 antagonists in the presence of LPS stimulation was investigated. The results revealed that ROS levels were increased and cell viability was decreased in LPS-stimulated pancreatic acinar cells. TLR4, Bax and PMAIP1 levels were increased, Bcl2 expression was decreased and NF-κB signaling was activated in LPS-stimulated pancreatic acinar cells. Furthermore, pancreatic cells with TLR4 overexpression exhibited increased ROS level and decreased viability. Finally, the effect caused by LPS stimulation was partially reversed by treatment of pancreatic acinar cells with TLR4 antagonists. In conclusion, the current study investigated a novel regulatory mechanism of the TLR4/NF-κB pathway in LPS-stimulated pancreatic cells, which may contribute to pancreatitis. The damage of these cells due to increased ROS levels was observed to occur through activation of the TLR4/NF-κB pathway.

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“…Pannexin-1 channels, a member of gap junction proteins involved in the innate and acquired immune system, could also contribute to the induction of inflammation and cognitive dysfunction of SAH via the TLR2/TLR4/NF-κB-mediated signaling pathways. Pannexin-1 channels protein gene knockdown significantly reduced the expression values of TLR2/4/ NF-κB signaling pathway in the neocortex and improved cognitive and memory deficits in a rat SAH model [143].…”

Section: The Role Of Toll-like Receptors In Subarrachnoid Hemorrhagementioning

confidence: 90%

The role of Toll-like receptor signaling pathways in cerebrovascular disorders: the impact of spreading depolarization

Ahmadabad

Ghadiri

Gorji

2020

J Neuroinflammation

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Cerebral vascular diseases (CVDs) are a group of disorders that affect the blood supply to the brain and lead to the reduction of oxygen and glucose supply to the neurons and the supporting cells. Spreading depolarization (SD), a propagating wave of neuroglial depolarization, occurs in different CVDs. A growing amount of evidence suggests that the inflammatory responses following hypoxic-ischemic insults and after SD plays a double-edged role in brain tissue injury and clinical outcome; a beneficial effect in the acute phase and a destructive role in the late phase. Toll-like receptors (TLRs) play a crucial role in the activation of inflammatory cascades and subsequent neuroprotective or harmful effects after CVDs and SD. Here, we review current data regarding the pathophysiological role of TLR signaling pathways in different CVDs and discuss the role of SD in the potentiation of the inflammatory cascade in CVDs through the modulation of TLRs.

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Roles of Pannexin-1 Channels in Inflammatory Response through the TLRs/NF-Kappa B Signaling Pathway Following Experimental Subarachnoid Hemorrhage in Rats

Cited by 49 publications

References 46 publications

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Endothelial pannexin 1 channels control inflammation by regulating intracellular calcium

Inflammatory stimuli promote oxidative stress in pancreatic acinar cells via Toll-like receptor 4/nuclear factor-κB pathway

The role of Toll-like receptor signaling pathways in cerebrovascular disorders: the impact of spreading depolarization

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