Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virus
Abstract Background Plasma gelsolin (pGSN) is an important part of the blood actin buffer that prevents negative consequences of possible F-actin deposition in the microcirculation and has various functions during host immune response. Recent reports reveal that severe COVID-19 correlates with reduc...
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| Format: | Article |
| Language: | English |
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BMC
2022-11-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-022-02642-4 |
| _version_ | 1797986637420953600 |
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| author | Łukasz Suprewicz Kiet A. Tran Ewelina Piktel Krzysztof Fiedoruk Paul A. Janmey Peter A. Galie Robert Bucki |
| author_facet | Łukasz Suprewicz Kiet A. Tran Ewelina Piktel Krzysztof Fiedoruk Paul A. Janmey Peter A. Galie Robert Bucki |
| author_sort | Łukasz Suprewicz |
| collection | DOAJ |
| description | Abstract Background Plasma gelsolin (pGSN) is an important part of the blood actin buffer that prevents negative consequences of possible F-actin deposition in the microcirculation and has various functions during host immune response. Recent reports reveal that severe COVID-19 correlates with reduced levels of pGSN. Therefore, using an in vitro system, we investigated whether pGSN could attenuate increased permeability of the blood–brain barrier (BBB) during its exposure to the portion of the SARS-CoV-2 spike protein containing the receptor binding domain (S1 subunit). Materials and methods Two- and three-dimensional models of the human BBB were constructed using the human cerebral microvascular endothelial cell line hCMEC/D3 and exposed to physiologically relevant shear stress to mimic perfusion in the central nervous system (CNS). Trans-endothelial electrical resistance (TEER) as well as immunostaining and Western blotting of tight junction (TJ) proteins assessed barrier integrity in the presence of the SARS-CoV-2 spike protein and pGSN. The IncuCyte Live Imaging system evaluated the motility of the endothelial cells. Magnetic bead-based ELISA was used to determine cytokine secretion. Additionally, quantitative real-time PCR (qRT-PCR) revealed gene expression of proteins from signaling pathways that are associated with the immune response. Results pGSN reversed S1-induced BBB permeability in both 2D and 3D BBB models in the presence of shear stress. BBB models exposed to pGSN also exhibited attenuated pro-inflammatory signaling pathways (PI3K, AKT, MAPK, NF-κB), reduced cytokine secretion (IL-6, IL-8, TNF-α), and increased expression of proteins that form intercellular TJ (ZO-1, occludin, claudin-5). Conclusion Due to its anti-inflammatory and protective effects on the brain endothelium, pGSN has the potential to be an alternative therapeutic target for patients with severe SARS-CoV-2 infection, especially those suffering neurological complications of COVID-19. |
| first_indexed | 2024-04-11T07:36:16Z |
| format | Article |
| id | doaj.art-443198935aff4306b3fd9dda4e87aa5c |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T07:36:16Z |
| publishDate | 2022-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-443198935aff4306b3fd9dda4e87aa5c2022-12-22T04:36:44ZengBMCJournal of Neuroinflammation1742-20942022-11-0119111610.1186/s12974-022-02642-4Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virusŁukasz Suprewicz0Kiet A. Tran1Ewelina Piktel2Krzysztof Fiedoruk3Paul A. Janmey4Peter A. Galie5Robert Bucki6Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of BiałystokDepartment of Biomedical Engineering, Rowan UniversityDepartment of Medical Microbiology and Nanobiomedical Engineering, Medical University of BiałystokDepartment of Medical Microbiology and Nanobiomedical Engineering, Medical University of BiałystokDepartment of Physiology and Institute for Medicine and Engineering, University of PennsylvaniaDepartment of Biomedical Engineering, Rowan UniversityDepartment of Medical Microbiology and Nanobiomedical Engineering, Medical University of BiałystokAbstract Background Plasma gelsolin (pGSN) is an important part of the blood actin buffer that prevents negative consequences of possible F-actin deposition in the microcirculation and has various functions during host immune response. Recent reports reveal that severe COVID-19 correlates with reduced levels of pGSN. Therefore, using an in vitro system, we investigated whether pGSN could attenuate increased permeability of the blood–brain barrier (BBB) during its exposure to the portion of the SARS-CoV-2 spike protein containing the receptor binding domain (S1 subunit). Materials and methods Two- and three-dimensional models of the human BBB were constructed using the human cerebral microvascular endothelial cell line hCMEC/D3 and exposed to physiologically relevant shear stress to mimic perfusion in the central nervous system (CNS). Trans-endothelial electrical resistance (TEER) as well as immunostaining and Western blotting of tight junction (TJ) proteins assessed barrier integrity in the presence of the SARS-CoV-2 spike protein and pGSN. The IncuCyte Live Imaging system evaluated the motility of the endothelial cells. Magnetic bead-based ELISA was used to determine cytokine secretion. Additionally, quantitative real-time PCR (qRT-PCR) revealed gene expression of proteins from signaling pathways that are associated with the immune response. Results pGSN reversed S1-induced BBB permeability in both 2D and 3D BBB models in the presence of shear stress. BBB models exposed to pGSN also exhibited attenuated pro-inflammatory signaling pathways (PI3K, AKT, MAPK, NF-κB), reduced cytokine secretion (IL-6, IL-8, TNF-α), and increased expression of proteins that form intercellular TJ (ZO-1, occludin, claudin-5). Conclusion Due to its anti-inflammatory and protective effects on the brain endothelium, pGSN has the potential to be an alternative therapeutic target for patients with severe SARS-CoV-2 infection, especially those suffering neurological complications of COVID-19.https://doi.org/10.1186/s12974-022-02642-4Plasma gelsolin (pGSN)COVID-19SARS-CoV-2Blood–brain barrierMicrofluidicsTissue engineering |
| spellingShingle | Łukasz Suprewicz Kiet A. Tran Ewelina Piktel Krzysztof Fiedoruk Paul A. Janmey Peter A. Galie Robert Bucki Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virus Journal of Neuroinflammation Plasma gelsolin (pGSN) COVID-19 SARS-CoV-2 Blood–brain barrier Microfluidics Tissue engineering |
| title | Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virus |
| title_full | Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virus |
| title_fullStr | Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virus |
| title_full_unstemmed | Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virus |
| title_short | Recombinant human plasma gelsolin reverses increased permeability of the blood–brain barrier induced by the spike protein of the SARS-CoV-2 virus |
| title_sort | recombinant human plasma gelsolin reverses increased permeability of the blood brain barrier induced by the spike protein of the sars cov 2 virus |
| topic | Plasma gelsolin (pGSN) COVID-19 SARS-CoV-2 Blood–brain barrier Microfluidics Tissue engineering |
| url | https://doi.org/10.1186/s12974-022-02642-4 |
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