In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model
Iron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1101387/full |
| _version_ | 1797852929113194496 |
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| author | Alexandra Gerogianni Alexandra Gerogianni Melissa Bal Melissa Bal Camilla Mohlin Camilla Mohlin Trent M. Woodruff John D. Lambris Tom E. Mollnes Tom E. Mollnes Tom E. Mollnes Dick J. Sjöström Dick J. Sjöström Per H. Nilsson Per H. Nilsson Per H. Nilsson |
| author_facet | Alexandra Gerogianni Alexandra Gerogianni Melissa Bal Melissa Bal Camilla Mohlin Camilla Mohlin Trent M. Woodruff John D. Lambris Tom E. Mollnes Tom E. Mollnes Tom E. Mollnes Dick J. Sjöström Dick J. Sjöström Per H. Nilsson Per H. Nilsson Per H. Nilsson |
| author_sort | Alexandra Gerogianni |
| collection | DOAJ |
| description | Iron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously found to induce the inflammatory response in human whole blood, including activation of the complement system and increased secretion of cytokines. Here, we investigated the thromboinflammatory response of 10-30 nm IONPs in lepirudin anticoagulated whole blood in interplay with endothelial cells and evaluated the therapeutic effect of applying complement inhibitors to limit adverse effects related to thromboinflammation. We found that IONPs induced complement activation, primarily at the C3-level, in whole blood incubated for up to four hours at 37°C with and without human microvascular endothelial cells. Furthermore, IONPs mediated a strong thromboinflammatory response, as seen by the significantly increased release of 21 of the 27 analyzed cytokines (p<0.05). IONPs also significantly increased cell-activation markers of endothelial cells [ICAM-1 (p<0.0001), P/E-selectin (p<0.05)], monocytes, and granulocytes [CD11b (p<0.001)], and platelets [CD62P (p<0.05), CD63 (p<0.05), NAP-2 (p<0.01), PF4 (p<0.05)], and showed cytotoxic effects, as seen by increased LDH (p<0.001) and heme (p<0.0001) levels. We found that inflammation and endothelial cell activation were partly complement-dependent and inhibition of complement at the level of C3 by compstatin Cp40 significantly attenuated expression of ICAM-1 (p<0.01) and selectins (p<0.05). We show that complement activation plays an important role in the IONPs-induced thromboinflammatory response and that complement inhibition is promising in improving IONPs biocompatibility. |
| first_indexed | 2024-04-09T19:41:12Z |
| format | Article |
| id | doaj.art-98f1b9d1f3a24517a729bb9b927be744 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-09T19:41:12Z |
| publishDate | 2023-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-98f1b9d1f3a24517a729bb9b927be7442023-04-04T05:40:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-04-011410.3389/fimmu.2023.11013871101387In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell modelAlexandra Gerogianni0Alexandra Gerogianni1Melissa Bal2Melissa Bal3Camilla Mohlin4Camilla Mohlin5Trent M. Woodruff6John D. Lambris7Tom E. Mollnes8Tom E. Mollnes9Tom E. Mollnes10Dick J. Sjöström11Dick J. Sjöström12Per H. Nilsson13Per H. Nilsson14Per H. Nilsson15Linnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, SwedenDepartment of Chemistry and Biomedicine, Linnaeus University, Kalmar, SwedenLinnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, SwedenDepartment of Chemistry and Biomedicine, Linnaeus University, Kalmar, SwedenLinnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, SwedenDepartment of Chemistry and Biomedicine, Linnaeus University, Kalmar, SwedenSchool of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, AustraliaDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United StatesDepartment of Immunology, Oslo University Hospital and University of Oslo, Oslo, NorwayCentre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, NorwayResearch Laboratory, Nordland Hospital, Bodo, NorwayLinnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, SwedenDepartment of Chemistry and Biomedicine, Linnaeus University, Kalmar, SwedenLinnaeus Centre for Biomaterials Chemistry, Linnaeus University, Kalmar, SwedenDepartment of Chemistry and Biomedicine, Linnaeus University, Kalmar, SwedenDepartment of Immunology, Oslo University Hospital and University of Oslo, Oslo, NorwayIron oxide nanoparticles (IONPs) are widely used in diagnostic and therapeutic settings. Upon systemic administration, however, they are rapidly recognized by components of innate immunity, which limit their therapeutic capacity and can potentially lead to adverse side effects. IONPs were previously found to induce the inflammatory response in human whole blood, including activation of the complement system and increased secretion of cytokines. Here, we investigated the thromboinflammatory response of 10-30 nm IONPs in lepirudin anticoagulated whole blood in interplay with endothelial cells and evaluated the therapeutic effect of applying complement inhibitors to limit adverse effects related to thromboinflammation. We found that IONPs induced complement activation, primarily at the C3-level, in whole blood incubated for up to four hours at 37°C with and without human microvascular endothelial cells. Furthermore, IONPs mediated a strong thromboinflammatory response, as seen by the significantly increased release of 21 of the 27 analyzed cytokines (p<0.05). IONPs also significantly increased cell-activation markers of endothelial cells [ICAM-1 (p<0.0001), P/E-selectin (p<0.05)], monocytes, and granulocytes [CD11b (p<0.001)], and platelets [CD62P (p<0.05), CD63 (p<0.05), NAP-2 (p<0.01), PF4 (p<0.05)], and showed cytotoxic effects, as seen by increased LDH (p<0.001) and heme (p<0.0001) levels. We found that inflammation and endothelial cell activation were partly complement-dependent and inhibition of complement at the level of C3 by compstatin Cp40 significantly attenuated expression of ICAM-1 (p<0.01) and selectins (p<0.05). We show that complement activation plays an important role in the IONPs-induced thromboinflammatory response and that complement inhibition is promising in improving IONPs biocompatibility.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1101387/fullthromboinflammationiron oxide nanoparticlesendothelial cellscomplement activationcomplement inhibitionwhole blood |
| spellingShingle | Alexandra Gerogianni Alexandra Gerogianni Melissa Bal Melissa Bal Camilla Mohlin Camilla Mohlin Trent M. Woodruff John D. Lambris Tom E. Mollnes Tom E. Mollnes Tom E. Mollnes Dick J. Sjöström Dick J. Sjöström Per H. Nilsson Per H. Nilsson Per H. Nilsson In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model Frontiers in Immunology thromboinflammation iron oxide nanoparticles endothelial cells complement activation complement inhibition whole blood |
| title | In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model |
| title_full | In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model |
| title_fullStr | In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model |
| title_full_unstemmed | In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model |
| title_short | In vitro evaluation of iron oxide nanoparticle-induced thromboinflammatory response using a combined human whole blood and endothelial cell model |
| title_sort | in vitro evaluation of iron oxide nanoparticle induced thromboinflammatory response using a combined human whole blood and endothelial cell model |
| topic | thromboinflammation iron oxide nanoparticles endothelial cells complement activation complement inhibition whole blood |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1101387/full |
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