Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis
Endothelial Tie2 signaling plays a pivotal role in vascular barrier maintenance at baseline and after injury. We previously demonstrated that a sharp drop in Tie2 expression observed across various murine models of critical illnesses is associated with increased vascular permeability and mortality....
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-08-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/59520 |
| _version_ | 1811252875825774592 |
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| author | Temitayo O Idowu Valerie Etzrodt Benjamin Seeliger Patricia Bolanos-Palmieri Kristina Thamm Hermann Haller Sascha David |
| author_facet | Temitayo O Idowu Valerie Etzrodt Benjamin Seeliger Patricia Bolanos-Palmieri Kristina Thamm Hermann Haller Sascha David |
| author_sort | Temitayo O Idowu |
| collection | DOAJ |
| description | Endothelial Tie2 signaling plays a pivotal role in vascular barrier maintenance at baseline and after injury. We previously demonstrated that a sharp drop in Tie2 expression observed across various murine models of critical illnesses is associated with increased vascular permeability and mortality. Matrix metalloprotease (MMP)−14-mediated Tie2 ectodomain shedding has recently been recognized as a possible mechanism for Tie2 downregulation in sepsis. Here, we identified the exact MMP14-mediated Tie2 ectodomain cleavage sites and could show that pharmacological MMP14 blockade in experimental murine sepsis exerts barrier protective and anti-inflammatory effects predominantly through the attenuation of Tie2 cleavage to improve survival both in a pre-treatment and rescue approach. Overall, we show that protecting Tie2 shedding might offer a new therapeutic opportunity for the treatment of septic vascular leakage. |
| first_indexed | 2024-04-12T16:42:12Z |
| format | Article |
| id | doaj.art-3c273d0291344f799a565c38b0b7ae32 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:42:12Z |
| publishDate | 2020-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-3c273d0291344f799a565c38b0b7ae322022-12-22T03:24:44ZengeLife Sciences Publications LtdeLife2050-084X2020-08-01910.7554/eLife.59520Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsisTemitayo O Idowu0https://orcid.org/0000-0002-3321-8589Valerie Etzrodt1Benjamin Seeliger2Patricia Bolanos-Palmieri3Kristina Thamm4Hermann Haller5Sascha David6https://orcid.org/0000-0002-8231-0461Department of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyDepartment of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyDepartment of Respiratory Medicine and German Centre of Lung Research (DZL), Hannover Medical School, Hannover, GermanyDepartment of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany; Department of Nephrology and Hypertension, University Hospital of Erlangen, Erlangen, GermanyDepartment of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyDepartment of Nephrology and Hypertension, Hannover Medical School, Hannover, GermanyDepartment of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany; Institute for Intensive Care, University Hospital Zurich, Zurich, SwitzerlandEndothelial Tie2 signaling plays a pivotal role in vascular barrier maintenance at baseline and after injury. We previously demonstrated that a sharp drop in Tie2 expression observed across various murine models of critical illnesses is associated with increased vascular permeability and mortality. Matrix metalloprotease (MMP)−14-mediated Tie2 ectodomain shedding has recently been recognized as a possible mechanism for Tie2 downregulation in sepsis. Here, we identified the exact MMP14-mediated Tie2 ectodomain cleavage sites and could show that pharmacological MMP14 blockade in experimental murine sepsis exerts barrier protective and anti-inflammatory effects predominantly through the attenuation of Tie2 cleavage to improve survival both in a pre-treatment and rescue approach. Overall, we show that protecting Tie2 shedding might offer a new therapeutic opportunity for the treatment of septic vascular leakage.https://elifesciences.org/articles/59520permeabilityvascular barrier functionTie2MMP14endothelial cellsSepsis |
| spellingShingle | Temitayo O Idowu Valerie Etzrodt Benjamin Seeliger Patricia Bolanos-Palmieri Kristina Thamm Hermann Haller Sascha David Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis eLife permeability vascular barrier function Tie2 MMP14 endothelial cells Sepsis |
| title | Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis |
| title_full | Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis |
| title_fullStr | Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis |
| title_full_unstemmed | Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis |
| title_short | Identification of specific Tie2 cleavage sites and therapeutic modulation in experimental sepsis |
| title_sort | identification of specific tie2 cleavage sites and therapeutic modulation in experimental sepsis |
| topic | permeability vascular barrier function Tie2 MMP14 endothelial cells Sepsis |
| url | https://elifesciences.org/articles/59520 |
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