IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury
Abstract Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripher...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02934-3 |
| _version_ | 1797414431988121600 |
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| author | Jonathan C. Vincent Colleen N. Garnett James B. Watson Emma K. Higgins Teresa Macheda Lydia Sanders Kelly N. Roberts Ryan K. Shahidehpour Eric M. Blalock Ning Quan Adam D. Bachstetter |
| author_facet | Jonathan C. Vincent Colleen N. Garnett James B. Watson Emma K. Higgins Teresa Macheda Lydia Sanders Kelly N. Roberts Ryan K. Shahidehpour Eric M. Blalock Ning Quan Adam D. Bachstetter |
| author_sort | Jonathan C. Vincent |
| collection | DOAJ |
| description | Abstract Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood–brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, corpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnfα. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health. |
| first_indexed | 2024-03-09T05:31:58Z |
| format | Article |
| id | doaj.art-1afd2662b1b249409d8005a54850aaee |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-09T05:31:58Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-1afd2662b1b249409d8005a54850aaee2023-12-03T12:31:11ZengBMCJournal of Neuroinflammation1742-20942023-10-0120111710.1186/s12974-023-02934-3IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injuryJonathan C. Vincent0Colleen N. Garnett1James B. Watson2Emma K. Higgins3Teresa Macheda4Lydia Sanders5Kelly N. Roberts6Ryan K. Shahidehpour7Eric M. Blalock8Ning Quan9Adam D. Bachstetter10Department of Neuroscience, University of KentuckyDepartment of Neuroscience, University of KentuckyDepartment of Neuroscience, University of KentuckyDepartment of Neuroscience, University of KentuckyDepartment of Neuroscience, University of KentuckyDepartment of Neuroscience, University of KentuckyDepartment of Neuroscience, University of KentuckyDepartment of Neuroscience, University of KentuckyDepartment of Pharmacology and Nutritional Sciences, University of KentuckyDepartment of Biomedical Science, Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic UniversityDepartment of Neuroscience, University of KentuckyAbstract Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood–brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, corpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnfα. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health.https://doi.org/10.1186/s12974-023-02934-3NeuroinflammationInterleukin-1Interleukin-1 receptor-1AstrocyteMicrogliaTraumatic brain injury |
| spellingShingle | Jonathan C. Vincent Colleen N. Garnett James B. Watson Emma K. Higgins Teresa Macheda Lydia Sanders Kelly N. Roberts Ryan K. Shahidehpour Eric M. Blalock Ning Quan Adam D. Bachstetter IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury Journal of Neuroinflammation Neuroinflammation Interleukin-1 Interleukin-1 receptor-1 Astrocyte Microglia Traumatic brain injury |
| title | IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury |
| title_full | IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury |
| title_fullStr | IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury |
| title_full_unstemmed | IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury |
| title_short | IL-1R1 signaling in TBI: assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed-head injury |
| title_sort | il 1r1 signaling in tbi assessing chronic impacts and neuroinflammatory dynamics in a mouse model of mild closed head injury |
| topic | Neuroinflammation Interleukin-1 Interleukin-1 receptor-1 Astrocyte Microglia Traumatic brain injury |
| url | https://doi.org/10.1186/s12974-023-02934-3 |
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