Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke
Abstract Background Activation of transforming growth factor-β-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-05-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1188-3 |
| _version_ | 1811192519121174528 |
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| author | Anjali Chauhan Jacob Hudobenko Abdullah Al Mamun Edward C. Koellhoffer Anthony Patrizz Rodney M. Ritzel Bhanu P. Ganesh Louise D. McCullough |
| author_facet | Anjali Chauhan Jacob Hudobenko Abdullah Al Mamun Edward C. Koellhoffer Anthony Patrizz Rodney M. Ritzel Bhanu P. Ganesh Louise D. McCullough |
| author_sort | Anjali Chauhan |
| collection | DOAJ |
| description | Abstract Background Activation of transforming growth factor-β-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which it is activated. There is a robust infiltration of myeloid cells after stroke; however, the contribution of myeloid TAK1 to cerebral ischemia is currently unknown. We hypothesized that myeloid-specific deletion of TAK1 would protect against ischemic brain injury. Methods Myeloid TAK1ΔM and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAo). Brain-infiltrating and splenic immune cells were evaluated at 3 days after stroke. Assessment of infarct size and behavioral deficits were performed on days 3 and 7 post-stroke. Results Infarcts were significantly smaller in TAK1ΔM mice (p < 0.01), and behavioral deficits were less severe despite equivalent reduction in cerebral blood flow. Flow cytometry demonstrated an increase in the frequency of splenic monocytes and neutrophils (p < 0.05) and a decrease in splenic CD3+ T (p < 0.01) and CD19+ B (p = 0.06) cells in TAK1ΔM mice compared to WT at baseline. Three days after stroke, a significant increase in the number of brain-infiltrating immune cell was observed in both TAK1ΔM (p < 0.05) and WT (p < 0.001) mice compared to their respective shams. However, there was a significant decrease in the infiltrating CD45hi immune cell counts (p < 0.05), with a pronounced reduction in infiltrating monocytes (p < 0.001) in TAK1ΔM after stroke compared to WT stroke mice. Additionally, a significant reduction in CD49d+ monocytes was seen in the brains of TAK1ΔM stroke mice compared to wild-type mice. Importantly, TAK1ΔM MCAo mice had smaller infarcts and improved behavioral outcomes at day 7 post-stroke. Conclusion Our results showed that deletion of myeloid TAK1 resulted in smaller infarcts and improved functional outcomes at the peak of inflammation (day 3) and a reduction in brain-infiltrating immune cells that were primarily monocytes. Myeloid TAK1 deletion was also protective at 7 days post MCAo, reflecting a detrimental role of myeloid TAK1 in the progression of ischemic injury. |
| first_indexed | 2024-04-11T23:53:49Z |
| format | Article |
| id | doaj.art-2f0052fd057c43039224e73613ab3e15 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-11T23:53:49Z |
| publishDate | 2018-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-2f0052fd057c43039224e73613ab3e152022-12-22T03:56:24ZengBMCJournal of Neuroinflammation1742-20942018-05-0115111010.1186/s12974-018-1188-3Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after strokeAnjali Chauhan0Jacob Hudobenko1Abdullah Al Mamun2Edward C. Koellhoffer3Anthony Patrizz4Rodney M. Ritzel5Bhanu P. GaneshLouise D. McCullough6Department of Neurology, University of Texas McGovern Medical School at HoustonDepartment of Neurology, University of Texas McGovern Medical School at HoustonDepartment of Neurology, University of Texas McGovern Medical School at HoustonDepartment of Neurology, University of Texas McGovern Medical School at HoustonDepartment of Neurology, University of Texas McGovern Medical School at HoustonDepartment of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research (STAR), University of Maryland School of MedicineDepartment of Neurology, University of Texas McGovern Medical School at HoustonAbstract Background Activation of transforming growth factor-β-activated kinase 1 (TAK1) occurs after stroke and leads to an exacerbation of brain injury. TAK1 is involved in innate and adaptive immune responses, but it has divergent inflammatory effects that are dependent on the cell type in which it is activated. There is a robust infiltration of myeloid cells after stroke; however, the contribution of myeloid TAK1 to cerebral ischemia is currently unknown. We hypothesized that myeloid-specific deletion of TAK1 would protect against ischemic brain injury. Methods Myeloid TAK1ΔM and wild-type (WT) mice were subjected to middle cerebral artery occlusion (MCAo). Brain-infiltrating and splenic immune cells were evaluated at 3 days after stroke. Assessment of infarct size and behavioral deficits were performed on days 3 and 7 post-stroke. Results Infarcts were significantly smaller in TAK1ΔM mice (p < 0.01), and behavioral deficits were less severe despite equivalent reduction in cerebral blood flow. Flow cytometry demonstrated an increase in the frequency of splenic monocytes and neutrophils (p < 0.05) and a decrease in splenic CD3+ T (p < 0.01) and CD19+ B (p = 0.06) cells in TAK1ΔM mice compared to WT at baseline. Three days after stroke, a significant increase in the number of brain-infiltrating immune cell was observed in both TAK1ΔM (p < 0.05) and WT (p < 0.001) mice compared to their respective shams. However, there was a significant decrease in the infiltrating CD45hi immune cell counts (p < 0.05), with a pronounced reduction in infiltrating monocytes (p < 0.001) in TAK1ΔM after stroke compared to WT stroke mice. Additionally, a significant reduction in CD49d+ monocytes was seen in the brains of TAK1ΔM stroke mice compared to wild-type mice. Importantly, TAK1ΔM MCAo mice had smaller infarcts and improved behavioral outcomes at day 7 post-stroke. Conclusion Our results showed that deletion of myeloid TAK1 resulted in smaller infarcts and improved functional outcomes at the peak of inflammation (day 3) and a reduction in brain-infiltrating immune cells that were primarily monocytes. Myeloid TAK1 deletion was also protective at 7 days post MCAo, reflecting a detrimental role of myeloid TAK1 in the progression of ischemic injury.http://link.springer.com/article/10.1186/s12974-018-1188-3Ischemic strokeMonocytesNeutrophilsInflammationTAK1 |
| spellingShingle | Anjali Chauhan Jacob Hudobenko Abdullah Al Mamun Edward C. Koellhoffer Anthony Patrizz Rodney M. Ritzel Bhanu P. Ganesh Louise D. McCullough Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke Journal of Neuroinflammation Ischemic stroke Monocytes Neutrophils Inflammation TAK1 |
| title | Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke |
| title_full | Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke |
| title_fullStr | Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke |
| title_full_unstemmed | Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke |
| title_short | Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke |
| title_sort | myeloid specific tak1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke |
| topic | Ischemic stroke Monocytes Neutrophils Inflammation TAK1 |
| url | http://link.springer.com/article/10.1186/s12974-018-1188-3 |
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