RelB and Neuroinflammation

Mockenhaupt, Karli; Gonsiewski, Alexandra K.; Kordula, Tomasz

doi:10.3390/cells10071609

Cited by 22 publications

(13 citation statements)

References 236 publications

(333 reference statements)

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“…In fact, TNF was the most up-regulated gene, with a 104-fold increase, followed by TNF-c (Lymphotoxin beta, LTB), with a 32.8-fold change ( Figure 3 , Table 1 ). Interestingly, LTB is a known inducer of the noncanonical NFκB inflammatory pathway [ 54 ] and was found to be up-regulated both at 6 and 24 h in SARS-CoV-2-exposed HBMEC by RT-qPCR ( Figure 3 E). Although our RNA-Seq data revealed an increase in NFκB2 (p100/p52) and NFκBIA (IκBα), we performed RT-qPCRs with additional biological samples for NF-κB1 (p105/p50) and NF-κB2 and observed that due to biological variability such genes remained unaltered in challenged cultures ( Figure 3 D).…”

Section: Resultsmentioning

confidence: 99%

Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling

Motta

Torices

Rosa

et al. 2023

Viruses

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Neurological effects of COVID-19 and long-COVID-19, as well as neuroinvasion by SARS-CoV-2, still pose several questions and are of both clinical and scientific relevance. We described the cellular and molecular effects of the human brain microvascular endothelial cells (HBMECs) in vitro exposure by SARS-CoV-2 to understand the underlying mechanisms of viral transmigration through the blood–brain barrier. Despite the low to non-productive viral replication, SARS-CoV-2-exposed cultures displayed increased immunoreactivity for cleaved caspase-3, an indicator of apoptotic cell death, tight junction protein expression, and immunolocalization. Transcriptomic profiling of SARS-CoV-2-challenged cultures revealed endothelial activation via NF-κB non-canonical pathway, including RELB overexpression and mitochondrial dysfunction. Additionally, SARS-CoV-2 led to altered secretion of key angiogenic factors and to significant changes in mitochondrial dynamics, with increased mitofusin-2 expression and increased mitochondrial networks. Endothelial activation and remodeling can further contribute to neuroinflammatory processes and lead to further BBB permeability in COVID-19.

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Section: Resultsmentioning

confidence: 99%

Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling

Motta

Torices

Rosa

et al. 2023

Viruses

View full text Add to dashboard Cite

show abstract

“…Although our RNA-Seq data revealed an increase in NFκB2 (p100/p52) and NFκBIA (IκBα), we performed RT-qPCRs with additional biological samples for NF-κB1 (p105/p50) and NF-κB2 and observed that, due to biological variability, such genes remained unaltered in infected cultures ( Figure 3D ). However, RELB, the main activator of noncanonical NF-κB signaling pathway (Mockenhaupt et al, 2021), was shown to be up-regulated by confirmatory RT-qPCR at 24 hpi ( Figure 4 ). We also further confirmed by RT-qPCR the up-regulation of inflammation-related genes, including LTB, TNF, IL-6, CXCL1, CXCL2 and CXCL8 ( Figure 3E ).…”

Section: Resultsmentioning

confidence: 86%

“…In fact, TNF was the most up-regulated gene, with 104-fold increase, followed by TNF-c (Lymphotoxin beta, LTB), with 32.8-fold change ( Figure 3, Table 1 ). Interestingly, LTB is a known inducer of noncanonical NFκB inflammatory pathway (Mockenhaupt et al, 2021) and was found to be up-regulated both at 6 and 24 hpi in SARS-CoV-2 infected HBMEC by RT-qPCR ( Figure 3E ). Although our RNA-Seq data revealed an increase in NFκB2 (p100/p52) and NFκBIA (IκBα), we performed RT-qPCRs with additional biological samples for NF-κB1 (p105/p50) and NF-κB2 and observed that, due to biological variability, such genes remained unaltered in infected cultures ( Figure 3D ).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the main protease of SARS-CoV-2 (M pro ) cleaves a member of the NF-κB family, NEMO, which in turn leads to HBMEC cell death in vitro and in vivo (Wenzel et al, 2021). RELB can form heterodimers with p50/p105, p52/p100 and p65 (Shih et al, 2012; reviewed by Mockenhaupt et al, 2021), but can also bind to sirtuin1 to direct epigenetic silencing of inflammatory gene expression (Chen et al, 2009; Liu et al, 2011). In fact, among KEGG pathways enriched in our datasets, we found ribosomal structure and function as possible candidates for epigenetic regulation induced by SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

SARS-CoV-2 infection of human brain microvascular endothelial cells leads to inflammatory activation through NF-κB non-canonical pathway and mitochondrial remodeling

Torices

Motta

Rosa

et al. 2022

Preprint

View full text Add to dashboard Cite

Neurological effects of COVID-19 and long-COVID-19 as well as neuroinvasion by SARS-CoV-2 still pose several questions and are of both clinical and scientific relevance. We described the cellular and molecular effects of the human brain microvascular endothelial cells (HBMECs) in vitro infection by SARS-CoV-2 to understand the underlying mechanisms of viral transmigration through the Blood-Brain Barrier. Despite the low to non- productive viral replication, SARS-CoV-2-infected cultures displayed increased apoptotic cell death and tight junction protein expression and immunolocalization. Transcriptomic profiling of infected cultures revealed endothelial activation via NF-κB non-canonical pathway, including RELB overexpression, and mitochondrial dysfunction. Additionally, SARS-CoV-2 led to altered secretion of key angiogenic factors and to significant changes in mitochondrial dynamics, with increased mitofusin-2 expression and increased mitochondrial networks. Endothelial activation and remodeling can further contribute to neuroinflammatory processes and lead to further BBB permeability in COVID-19.

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“…The performance trends of TLR-4 and NF-κB are not consistent, which may be derived from various triggers of the canonical NF-κB pathway. In addition to cell surface receptors such as toll-like receptors (TLRs), proinflammatory cytokines and T cell receptors or B cell receptors can trigger NF-κB pathway as well ( 41 , 42 ). In addition, GAFP levels and pro-inflammatory cytokine IL-1β secretion increased after AQP2 overexpression.…”

Section: Discussionmentioning

confidence: 99%

AQP2 Promotes Astrocyte Activation by Modulating the TLR4/NFκB-p65 Pathway Following Intracerebral Hemorrhage

et al. 2022

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Microglial and astrocyte activation and related cytokine secretion play key roles in secondary brain injury following intracerebral hemorrhage (ICH). We assessed the role of aquaporin (AQP)2 in immune response after ICH. We prospectively collected data from 33 patients with ICH and analyzed the serum AQP2 levels in these patients and age-matched healthy controls. A correlation analysis was also performed between patient serum AQP2 levels and clinical factors. In the rat ICH model, double-fluorescence staining for glial fibrillary acidic protein (GFAP) and AQP2 was performed to investigate the relationship between astrocytes and AQP2. Relative mRNA expression levels of GFAP and AQP2 were also measured. In the rat astrocyte cell line CTX-TNA2, toll-like receptor (TLR)4/nuclear factor kappa B (NFκB)-p65 pathway activation and GFAP levels were measured. The indirect influence of AQP2 on microglial polarization was assessed following exposure to the medium of astrocytes treated with AQP2-overexpression plasmid or silencing RNA. We found that the serum AQP2 expression was lower in patients with ICH. Sex and blood neutrophil count influenced serum AQP2 concentrations in patients with ICH on admission. Lower serum AQP2 levels were inversely correlated with 90-day Modified Rankin Scale scores after ICH, but were not correlated with National Institute of Health stroke scale (NIHSS) scores on admission. AQP2 overexpression and localization in GFAP-labeled astrocytes were observed in rats. AQP2 overexpression induced astrocyte activation with GFAP upregulation via TLR/NFκB-p65 signaling pathway activation in the rat astrocyte cell line CTX-TNA2. Astrocyte activation promoted interleukin-1β secretion. The medium of AQP2-overexpression astrocytes promoted the pro-inflammatory M1 phenotype in the immortal rat (HAPI) microglial cell line. Therefore, serum AQP2 is negatively correlated with post-ICH prognosis and may be a marker of inflammation in early-stage ICH. AQP2 overexpression promotes astrocyte activation and pro-inflammatory secretion, affects astrocyte-microglia crosstalk, and indirectly induces microglial polarization, which may augment inflammation after ICH.

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RelB and Neuroinflammation

Cited by 22 publications

References 236 publications

Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling

Human Brain Microvascular Endothelial Cells Exposure to SARS-CoV-2 Leads to Inflammatory Activation through NF-κB Non-Canonical Pathway and Mitochondrial Remodeling

SARS-CoV-2 infection of human brain microvascular endothelial cells leads to inflammatory activation through NF-κB non-canonical pathway and mitochondrial remodeling

AQP2 Promotes Astrocyte Activation by Modulating the TLR4/NFκB-p65 Pathway Following Intracerebral Hemorrhage

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