Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding
Sepsis is caused by a dysregulated immune response to infection and is a leading cause of mortality globally. To date, no specific therapeutics are available to treat the underlying septic response. We and others have shown that recombinant human annexin A5 (Anx5) treatment inhibits pro-inflammatory...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-06-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/6/837 |
| _version_ | 1797593148049850368 |
|---|---|
| author | Brent J. Tschirhart Xiangru Lu Janice Gomes Arundhasa Chandrabalan Gillian Bell David A. Hess Guangxin Xing Hong Ling Dylan Burger Qingping Feng |
| author_facet | Brent J. Tschirhart Xiangru Lu Janice Gomes Arundhasa Chandrabalan Gillian Bell David A. Hess Guangxin Xing Hong Ling Dylan Burger Qingping Feng |
| author_sort | Brent J. Tschirhart |
| collection | DOAJ |
| description | Sepsis is caused by a dysregulated immune response to infection and is a leading cause of mortality globally. To date, no specific therapeutics are available to treat the underlying septic response. We and others have shown that recombinant human annexin A5 (Anx5) treatment inhibits pro-inflammatory cytokine production and improves survival in rodent sepsis models. During sepsis, activated platelets release microvesicles (MVs) with externalization of phosphatidylserine to which Anx5 binds with high affinity. We hypothesized that recombinant human Anx5 blocks the pro-inflammatory response induced by activated platelets and MVs in vascular endothelial cells under septic conditions via phosphatidylserine binding. Our data show that treatment with wildtype Anx5 reduced the expression of inflammatory cytokines and adhesion molecules induced by lipopolysaccharide (LPS)-activated platelets or MVs in endothelial cells (<i>p</i> < 0.01), which was not observed with Anx5 mutant deficient in phosphatidylserine binding. In addition, wildtype Anx5 treatment, but not Anx5 mutant, improved trans-endothelial electrical resistance (<i>p</i> < 0.05) and reduced monocyte (<i>p</i> < 0.001) and platelet (<i>p</i> < 0.001) adhesion to vascular endothelial cells in septic conditions. In conclusion, recombinant human Anx5 inhibits endothelial inflammation induced by activated platelets and MVs in septic conditions via phosphatidylserine binding, which may contribute to its anti-inflammatory effects in the treatment of sepsis. |
| first_indexed | 2024-03-11T02:03:45Z |
| format | Article |
| id | doaj.art-ecf56b9a0f834f0e975f87e24fd79aa6 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T02:03:45Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-ecf56b9a0f834f0e975f87e24fd79aa62023-11-18T12:02:13ZengMDPI AGPharmaceuticals1424-82472023-06-0116683710.3390/ph16060837Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine BindingBrent J. Tschirhart0Xiangru Lu1Janice Gomes2Arundhasa Chandrabalan3Gillian Bell4David A. Hess5Guangxin Xing6Hong Ling7Dylan Burger8Qingping Feng9Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaRobarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaRobarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaDepartment of Biochemistry, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaKidney Research Centre, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON K1H 8L6, CanadaDepartment of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, CanadaSepsis is caused by a dysregulated immune response to infection and is a leading cause of mortality globally. To date, no specific therapeutics are available to treat the underlying septic response. We and others have shown that recombinant human annexin A5 (Anx5) treatment inhibits pro-inflammatory cytokine production and improves survival in rodent sepsis models. During sepsis, activated platelets release microvesicles (MVs) with externalization of phosphatidylserine to which Anx5 binds with high affinity. We hypothesized that recombinant human Anx5 blocks the pro-inflammatory response induced by activated platelets and MVs in vascular endothelial cells under septic conditions via phosphatidylserine binding. Our data show that treatment with wildtype Anx5 reduced the expression of inflammatory cytokines and adhesion molecules induced by lipopolysaccharide (LPS)-activated platelets or MVs in endothelial cells (<i>p</i> < 0.01), which was not observed with Anx5 mutant deficient in phosphatidylserine binding. In addition, wildtype Anx5 treatment, but not Anx5 mutant, improved trans-endothelial electrical resistance (<i>p</i> < 0.05) and reduced monocyte (<i>p</i> < 0.001) and platelet (<i>p</i> < 0.001) adhesion to vascular endothelial cells in septic conditions. In conclusion, recombinant human Anx5 inhibits endothelial inflammation induced by activated platelets and MVs in septic conditions via phosphatidylserine binding, which may contribute to its anti-inflammatory effects in the treatment of sepsis.https://www.mdpi.com/1424-8247/16/6/837sepsisendotoxemiainflammationannexin A5endothelial cellsplatelets |
| spellingShingle | Brent J. Tschirhart Xiangru Lu Janice Gomes Arundhasa Chandrabalan Gillian Bell David A. Hess Guangxin Xing Hong Ling Dylan Burger Qingping Feng Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding Pharmaceuticals sepsis endotoxemia inflammation annexin A5 endothelial cells platelets |
| title | Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding |
| title_full | Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding |
| title_fullStr | Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding |
| title_full_unstemmed | Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding |
| title_short | Annexin A5 Inhibits Endothelial Inflammation Induced by Lipopolysaccharide-Activated Platelets and Microvesicles via Phosphatidylserine Binding |
| title_sort | annexin a5 inhibits endothelial inflammation induced by lipopolysaccharide activated platelets and microvesicles via phosphatidylserine binding |
| topic | sepsis endotoxemia inflammation annexin A5 endothelial cells platelets |
| url | https://www.mdpi.com/1424-8247/16/6/837 |
| work_keys_str_mv | AT brentjtschirhart annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT xiangrulu annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT janicegomes annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT arundhasachandrabalan annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT gillianbell annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT davidahess annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT guangxinxing annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT hongling annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT dylanburger annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding AT qingpingfeng annexina5inhibitsendothelialinflammationinducedbylipopolysaccharideactivatedplateletsandmicrovesiclesviaphosphatidylserinebinding |