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

Motta, Carolline Soares; Torices, Silvia; Rosa, Bárbara Gomes da; Marcos, Anne Caroline; Alvarez-Rosa, Liandra; Siqueira, Michele; Moreno-Rodriguez, Thaidy; Matos, Aline da Rocha; Caetano, Bráulia Costa; Martins, Jessica; Gladulich, Luis; Loiola, Erick Correia; Bagshaw, Olivia R.M.; Stuart, Jeffrey A.; Siqueira, Marilda Mendonça; Stipursky, Joice; Toborek, Michał; Adesse, Daniel

doi:10.3390/v15030745

Cited by 14 publications

(10 citation statements)

References 136 publications

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“…We observed an increase in brain endothelial cell VCAM-1 in acute SARS-CoV-2 infection. This is similar to reports of upregulated leukocyte adhesion molecules in the cerebrovasculature of patients with severe acute COVID-19 (Savarraj et al, 2021; Thakur et al, 2023; Zhou et al, 2021) and in cultured brain endothelial cells exposed to SARS-CoV-2 virions or proteins (Buzhdygan et al, 2020; Constant et al, 2021; Motta et al, 2023; Yang et al, 2022). These findings fit within a larger context of brain endothelial hyperinflammatory responses and systemic inflammation in COVID-19 (Bonetto et al, 2022; Frere et al, 2022; Israelow et al, 2020; Pilotto et al, 2021; Rutkai et al, 2022; Soung et al ., 2022).…”

Section: Discussionsupporting

confidence: 90%

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

Trevino,

Fogel,

Minshall

et al. 2023

Preprint

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Leukocyte infiltration of the CNS can contribute to neuroinflammation and cognitive impairment. Brain endothelial cells regulate adhesion, activation, and diapedesis of T cells across the blood-brain barrier (BBB) in inflammatory diseases. The integral membrane protein Caveolin-1 (Cav-1) critically regulates BBB permeability, but its influence on T cell CNS infiltration in respiratory viral infections is unknown. In this study, we sought to determine the role of Cav-1 at the BBB in neuroinflammation in a COVID-19 mouse model. We used mice genetically deficient in Cav-1 to test the role of this protein in T cell infiltration and cognitive impairment. We found that SARS-CoV-2 infection upregulated brain endothelial Cav-1. Moreover, SARS-CoV-2 infection increased brain endothelial cell vascular cell adhesion molecule-1 (VCAM-1) and CD3+ T cell infiltration of the hippocampus, a region important for short term learning and memory. Concordantly, we observed learning and memory deficits. Importantly, genetic deficiency in Cav-1 attenuated brain endothelial VCAM-1 expression and T cell infiltration in the hippocampus of mice with SARS-CoV-2 infection. Moreover, Cav-1 KO mice were protected from the learning and memory deficits caused by SARS-CoV-2 infection. These results indicate the importance of BBB permeability in COVID-19 neuroinflammation and suggest potential therapeutic value of targeting Cav-1 to improve disease outcomes.

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Section: Discussionsupporting

confidence: 90%

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

Trevino,

Fogel,

Minshall

et al. 2023

Preprint

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“…We have previously shown that cells of the NVU express the known receptors required for SARS-CoV-2 to enter host cells, including ACE2 and TMPRSS2 [ 6 ]. However, several laboratories, including our group, failed to demonstrate any productive SARS-CoV-2 replication in brain endothelial cells [ 38 ], [ 39 ], [ 40 ]. While a productive infection has recently been reported in human induced pluripotent stem cell-derived brain capillary endothelial-like cells, this was achieved only after employing a high multiplicity of infection (MOI) 10, which questions the pathological relevance of these findings [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…IL-6 is a key cytokine in BBB integrity and is a hallmark of neuroinflammatory processes [ 44 ]. Our group published recently that immortalized HBMEC exposed to SARS-CoV-2 have increased IL-6 gene expression [ 38 ]. The results of the current study indicate that treatment of HBMEC with the S1 subunit markedly upregulated the release of IL-6.…”

Section: Discussionmentioning

confidence: 99%

The S1 subunits of SARS-CoV-2 variants differentially trigger the IL-6 signaling pathway in human brain endothelial cells and downstream impact on microglia activation

Stangis,

Adesse,

Sharma

et al. 2024

NeuroImmune Pharmacology and Therapeutics

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Objectives Cerebrovascular complications are prevalent in COVID-19 infection and post-COVID conditions; therefore, interactions of SARS-CoV-2 with cerebral microvascular cells became an emerging concern. Methods We examined the inflammatory responses of human brain microvascular endothelial cells (HBMEC), the main structural element of the blood–brain barrier (BBB), following exposure to the S1 subunit of the spike protein of different SARS-CoV-2 variants. Specifically, we used the S1 subunit derived from the D614 variant of SARS-CoV-2, which started widely circulating in March of 2020, and from the Delta variant, which started widely circulating in early 2021. We then further examined the impact of the HBMEC secretome, produced in response to the S1 exposure, on microglial proinflammatory responses. Results Treatment with S1 derived from the D614 variant and from the Delta variant resulted in differential alterations of the IL-6 signaling pathway. Moreover, the HBMEC secretome obtained after exposure to the S1 subunit of the D614 variant activated STAT3 in microglial cells, indicating that proinflammatory signals from endothelial cells can propagate to other cells of the neurovascular unit. Overall, these results indicate the potential for different SARS-CoV-2 variants to induce unique cellular signatures and warrant individualized treatment strategies. The findings from this study also bring further awareness to proinflammatory responses involving brain microvasculature in COVID-19 and demonstrate how the surrounding microglia react to each unique variant derived response.

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“…Similar to bacteria, systemic viral infections often lead to marked expression of proinflammatory cytokines and vascular complications, such as thrombosis and/or hypoxemia ( Ishiguro et al, 2019 ; Pajo et al, 2021 ; Neufeldt et al, 2022 ; Motta et al, 2023 ). A recent example of this is infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the etiological agent of coronavirus disease 2019 (COVID-19).…”

Section: Systemic Inflammationmentioning

confidence: 99%

Microglia at the blood brain barrier in health and disease

Mayer,

Fischer

2024

Front. Cell. Neurosci.

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The blood brain barrier (BBB) plays a crucial role in maintaining brain homeostasis by selectively preventing the entry of substances from the peripheral blood into the central nervous system (CNS). Comprised of endothelial cells, pericytes, and astrocytes, this highly regulated barrier encompasses the majority of the brain’s vasculature. In addition to its protective function, the BBB also engages in significant crosstalk with perivascular macrophages (MΦ) and microglia, the resident MΦ of the brain. These interactions play a pivotal role in modulating the activation state of cells comprising the BBB, as well as MΦs and microglia, themselves. Alterations in systemic metabolic and inflammatory states can promote endothelial cell dysfunction, reducing the integrity of the BBB and potentially allowing peripheral blood factors to leak into the CNS compartment. This may mediate activation of perivascular MΦs, microglia, and astrocytes, and initiate further immune responses within the brain parenchyma, suggesting neuroinflammation can be triggered by signaling from the periphery, without primary injury or disease originating within the CNS. The intricate interplay between the periphery and the CNS through the BBB highlights the importance of understanding the role of microglia in mediating responses to systemic challenges. Despite recent advancements, our understanding of the interactions between microglia and the BBB is still in its early stages, leaving a significant gap in knowledge. However, emerging research is shedding light on the involvement of microglia at the BBB in various conditions, including systemic infections, diabetes, and ischemic stroke. This review aims to provide a comprehensive overview of the current research investigating the intricate relationship between microglia and the BBB in health and disease. By exploring these connections, we hope to advance our understanding of the role of brain immune responses to systemic challenges and their impact on CNS health and pathology. Uncovering these interactions may hold promise for the development of novel therapeutic strategies for neurological conditions that involve immune and vascular mechanisms.

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

Cited by 14 publications

References 136 publications

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

Caveolin-1 mediates neuroinflammation and cognitive impairment in SARS-CoV-2 infection

The S1 subunits of SARS-CoV-2 variants differentially trigger the IL-6 signaling pathway in human brain endothelial cells and downstream impact on microglia activation

Microglia at the blood brain barrier in health and disease

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