Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemia
Background: The well-characterised role of the immune system in acute ischaemic stroke has prompted the search for immunomodulatory therapies. Pregnancy-specific glycoproteins (PSGs) are a group of proteins synthesised by placental trophoblasts which show immunomodulatory properties. The aim of this...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Brain, Behavior, & Immunity - Health |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666354622000874 |
| _version_ | 1811254845721542656 |
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| author | Kyle Malone Jennifer A. Shearer John M. Williams Anne C. Moore Tom Moore Christian Waeber |
| author_facet | Kyle Malone Jennifer A. Shearer John M. Williams Anne C. Moore Tom Moore Christian Waeber |
| author_sort | Kyle Malone |
| collection | DOAJ |
| description | Background: The well-characterised role of the immune system in acute ischaemic stroke has prompted the search for immunomodulatory therapies. Pregnancy-specific glycoproteins (PSGs) are a group of proteins synthesised by placental trophoblasts which show immunomodulatory properties. The aim of this study was to determine whether a proposed PSG1-based therapeutic enhanced recovery in a mouse model of brain ischaemia and to explore possible immunomodulatory effects. Methods: Mice underwent permanent electrocoagulation of the left middle cerebral artery (pMCAO). They received saline (n = 20) or recombinant pregnancy-specific glycoprotein-1-alpha “fused” to the Fc domain of IgG1 (rPSG1-Fc) (100 μg) (n = 22) at 1 h post-ischaemia. At 3 and 5 days post-ischaemia, neurobehavioural recovery was assessed by the grid-walking test. At 5 days post-ischaemia, lesion size was determined by NeuN staining. Peripheral T cell populations were quantified via flow cytometry. Immunohistochemistry was used to quantify ICAM-1 expression and FoxP3+ cell infiltration in the ischaemic brain. Immunofluorescence was employed to determine microglial activation status via Iba-1 staining.Results: rPSG1-Fc significantly enhanced performance in the grid-walking test at 3 and 5 days post-ischaemia. No effect on infarct size was observed. A significant increase in circulating CD4+ FoxP3+ cells and brain-infiltrating FoxP3+ cells was noted in rPSG1-Fc-treated mice. Among CD4+ cells, rPSG1-Fc enhanced the expression of IL-10 in spleen, blood, draining lymph nodes, and non-draining lymph nodes, while downregulating IFN-γ and IL-17 in spleen and blood. A similar cytokine expression pattern was observed in CD8+ cells. rPSG1-Fc reduced activated microglia in the infarct core. Conclusion: The administration of rPSG1-Fc improved functional recovery in post-ischaemic mice without impacting infarct size. Improved outcome was associated with a modulation of the cytokine-secreting phenotype of CD4+ and CD8+ T cells towards a more regulatory phenotype, as well as reduced activation of microglia. This establishes proof-of-concept of rPSG1-Fc as a potential stroke immunotherapy. |
| first_indexed | 2024-04-12T17:13:52Z |
| format | Article |
| id | doaj.art-3cbd3c0371184b83ab73e99729480390 |
| institution | Directory Open Access Journal |
| issn | 2666-3546 |
| language | English |
| last_indexed | 2024-04-12T17:13:52Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Brain, Behavior, & Immunity - Health |
| spelling | doaj.art-3cbd3c0371184b83ab73e997294803902022-12-22T03:23:43ZengElsevierBrain, Behavior, & Immunity - Health2666-35462022-11-0125100497Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemiaKyle Malone0Jennifer A. Shearer1John M. Williams2Anne C. Moore3Tom Moore4Christian Waeber5Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland; Corresponding author. Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Ireland.Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, IrelandSchool of Biochemistry and Cell Biology, University College Cork, Cork, IrelandSchool of Biochemistry and Cell Biology, University College Cork, Cork, IrelandSchool of Biochemistry and Cell Biology, University College Cork, Cork, Ireland; Corresponding author. School of Pharmacy, University College Cork, Cork, Ireland.Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cork, Ireland; Corresponding author. School of Pharmacy, University College Cork, Cork, Ireland.Background: The well-characterised role of the immune system in acute ischaemic stroke has prompted the search for immunomodulatory therapies. Pregnancy-specific glycoproteins (PSGs) are a group of proteins synthesised by placental trophoblasts which show immunomodulatory properties. The aim of this study was to determine whether a proposed PSG1-based therapeutic enhanced recovery in a mouse model of brain ischaemia and to explore possible immunomodulatory effects. Methods: Mice underwent permanent electrocoagulation of the left middle cerebral artery (pMCAO). They received saline (n = 20) or recombinant pregnancy-specific glycoprotein-1-alpha “fused” to the Fc domain of IgG1 (rPSG1-Fc) (100 μg) (n = 22) at 1 h post-ischaemia. At 3 and 5 days post-ischaemia, neurobehavioural recovery was assessed by the grid-walking test. At 5 days post-ischaemia, lesion size was determined by NeuN staining. Peripheral T cell populations were quantified via flow cytometry. Immunohistochemistry was used to quantify ICAM-1 expression and FoxP3+ cell infiltration in the ischaemic brain. Immunofluorescence was employed to determine microglial activation status via Iba-1 staining.Results: rPSG1-Fc significantly enhanced performance in the grid-walking test at 3 and 5 days post-ischaemia. No effect on infarct size was observed. A significant increase in circulating CD4+ FoxP3+ cells and brain-infiltrating FoxP3+ cells was noted in rPSG1-Fc-treated mice. Among CD4+ cells, rPSG1-Fc enhanced the expression of IL-10 in spleen, blood, draining lymph nodes, and non-draining lymph nodes, while downregulating IFN-γ and IL-17 in spleen and blood. A similar cytokine expression pattern was observed in CD8+ cells. rPSG1-Fc reduced activated microglia in the infarct core. Conclusion: The administration of rPSG1-Fc improved functional recovery in post-ischaemic mice without impacting infarct size. Improved outcome was associated with a modulation of the cytokine-secreting phenotype of CD4+ and CD8+ T cells towards a more regulatory phenotype, as well as reduced activation of microglia. This establishes proof-of-concept of rPSG1-Fc as a potential stroke immunotherapy.http://www.sciencedirect.com/science/article/pii/S2666354622000874StrokeImmunomodulationIschaemiaRegulatory T cellsPregnancy-specific glycoproteinPSG1 |
| spellingShingle | Kyle Malone Jennifer A. Shearer John M. Williams Anne C. Moore Tom Moore Christian Waeber Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemia Brain, Behavior, & Immunity - Health Stroke Immunomodulation Ischaemia Regulatory T cells Pregnancy-specific glycoprotein PSG1 |
| title | Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemia |
| title_full | Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemia |
| title_fullStr | Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemia |
| title_full_unstemmed | Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemia |
| title_short | Recombinant pregnancy-specific glycoprotein-1-Fc reduces functional deficit in a mouse model of permanent brain ischaemia |
| title_sort | recombinant pregnancy specific glycoprotein 1 fc reduces functional deficit in a mouse model of permanent brain ischaemia |
| topic | Stroke Immunomodulation Ischaemia Regulatory T cells Pregnancy-specific glycoprotein PSG1 |
| url | http://www.sciencedirect.com/science/article/pii/S2666354622000874 |
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