Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice
Spinal cord injury (SCI) is a devastating condition consisting of an instant primary mechanical injury followed by a secondary injury that progresses for weeks to months. The cytokine tumor necrosis factor (TNF) plays an important role in the pathophysiology of SCI. We investigated the effect of mye...
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MDPI AG
2020-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/11/2407 |
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| author | Ditte Gry Ellman Minna Christiansen Lund Maiken Nissen Pernille Sveistrup Nielsen Charlotte Sørensen Emilie Boye Lester Estrid Thougaard Louise Helskov Jørgensen Sergei A. Nedospasov Ditte Caroline Andersen Jane Stubbe Roberta Brambilla Matilda Degn Kate Lykke Lambertsen |
| author_facet | Ditte Gry Ellman Minna Christiansen Lund Maiken Nissen Pernille Sveistrup Nielsen Charlotte Sørensen Emilie Boye Lester Estrid Thougaard Louise Helskov Jørgensen Sergei A. Nedospasov Ditte Caroline Andersen Jane Stubbe Roberta Brambilla Matilda Degn Kate Lykke Lambertsen |
| author_sort | Ditte Gry Ellman |
| collection | DOAJ |
| description | Spinal cord injury (SCI) is a devastating condition consisting of an instant primary mechanical injury followed by a secondary injury that progresses for weeks to months. The cytokine tumor necrosis factor (TNF) plays an important role in the pathophysiology of SCI. We investigated the effect of myeloid TNF ablation (peripheral myeloid cells (macrophages and neutrophils) and microglia) versus central myeloid TNF ablation (microglia) in a SCI contusion model. We show that TNF ablation in macrophages and neutrophils leads to reduced lesion volume and improved functional outcome after SCI. In contrast, TNF ablation in microglia only or TNF deficiency in all cells had no effect. TNF levels tended to be decreased 3 h post-SCI in mice with peripheral myeloid TNF ablation and was significantly decreased 3 days after SCI. Leukocyte and microglia populations and all other cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and IFNγ) and chemokines (CCL2, CCL5, and CXCL1) investigated, in addition to TNFR1 and TNFR2, were comparable between genotypes. Analysis of post-SCI signaling cascades demonstrated that the MAPK kinase SAPK/JNK decreased and neuronal Bcl-XL levels increased post-SCI in mice with ablation of TNF in peripheral myeloid cells. These findings demonstrate that peripheral myeloid cell-derived TNF is pathogenic in SCI. |
| first_indexed | 2024-03-10T15:07:56Z |
| format | Article |
| id | doaj.art-584fac6ad7c546a4ac7842a8f872810c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T15:07:56Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-584fac6ad7c546a4ac7842a8f872810c2023-11-20T19:36:04ZengMDPI AGCells2073-44092020-11-01911240710.3390/cells9112407Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in MiceDitte Gry Ellman0Minna Christiansen Lund1Maiken Nissen2Pernille Sveistrup Nielsen3Charlotte Sørensen4Emilie Boye Lester5Estrid Thougaard6Louise Helskov Jørgensen7Sergei A. Nedospasov8Ditte Caroline Andersen9Jane Stubbe10Roberta Brambilla11Matilda Degn12Kate Lykke Lambertsen13Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Clinical Research, University of Southern Denmark, 5000 Odense, DenmarkEngelhardt Institute of Molecular Biology, Russian Academy of Sciences and Lomonosov Moscow State University, 119991 Moscow, RussiaDepartment of Clinical Research, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkPediatric Oncology Laboratory, Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, 2100 Copenhagen, DenmarkDepartment of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, 5000 Odense, DenmarkSpinal cord injury (SCI) is a devastating condition consisting of an instant primary mechanical injury followed by a secondary injury that progresses for weeks to months. The cytokine tumor necrosis factor (TNF) plays an important role in the pathophysiology of SCI. We investigated the effect of myeloid TNF ablation (peripheral myeloid cells (macrophages and neutrophils) and microglia) versus central myeloid TNF ablation (microglia) in a SCI contusion model. We show that TNF ablation in macrophages and neutrophils leads to reduced lesion volume and improved functional outcome after SCI. In contrast, TNF ablation in microglia only or TNF deficiency in all cells had no effect. TNF levels tended to be decreased 3 h post-SCI in mice with peripheral myeloid TNF ablation and was significantly decreased 3 days after SCI. Leukocyte and microglia populations and all other cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, and IFNγ) and chemokines (CCL2, CCL5, and CXCL1) investigated, in addition to TNFR1 and TNFR2, were comparable between genotypes. Analysis of post-SCI signaling cascades demonstrated that the MAPK kinase SAPK/JNK decreased and neuronal Bcl-XL levels increased post-SCI in mice with ablation of TNF in peripheral myeloid cells. These findings demonstrate that peripheral myeloid cell-derived TNF is pathogenic in SCI.https://www.mdpi.com/2073-4409/9/11/2407tumor necrosis factorspinal cord injurymyeloid cellsfunctional outcome |
| spellingShingle | Ditte Gry Ellman Minna Christiansen Lund Maiken Nissen Pernille Sveistrup Nielsen Charlotte Sørensen Emilie Boye Lester Estrid Thougaard Louise Helskov Jørgensen Sergei A. Nedospasov Ditte Caroline Andersen Jane Stubbe Roberta Brambilla Matilda Degn Kate Lykke Lambertsen Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice Cells tumor necrosis factor spinal cord injury myeloid cells functional outcome |
| title | Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice |
| title_full | Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice |
| title_fullStr | Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice |
| title_full_unstemmed | Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice |
| title_short | Conditional Ablation of Myeloid TNF Improves Functional Outcome and Decreases Lesion Size after Spinal Cord Injury in Mice |
| title_sort | conditional ablation of myeloid tnf improves functional outcome and decreases lesion size after spinal cord injury in mice |
| topic | tumor necrosis factor spinal cord injury myeloid cells functional outcome |
| url | https://www.mdpi.com/2073-4409/9/11/2407 |
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