Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states
Abstract Background Rehabilitative training is an effective method to promote recovery following spinal cord injury (SCI), with lower training efficacy observed in the chronic stage. The increased training efficacy during the subacute period is associated with a shift towards a more adaptive or pror...
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BMC
2025-02-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | https://doi.org/10.1186/s12974-025-03379-6 |
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| author | Rebecca K. John Sadie P. Vogel Sameera Zia Kelly V. Lee Antoinette T. Nguyen Abel Torres-Espin Keith K. Fenrich Carmen Ng Emma K. A. Schmidt Romana Vavrek Pamela J. F. Raposo Keira Smith Karim Fouad Jason R. Plemel |
| author_facet | Rebecca K. John Sadie P. Vogel Sameera Zia Kelly V. Lee Antoinette T. Nguyen Abel Torres-Espin Keith K. Fenrich Carmen Ng Emma K. A. Schmidt Romana Vavrek Pamela J. F. Raposo Keira Smith Karim Fouad Jason R. Plemel |
| author_sort | Rebecca K. John |
| collection | DOAJ |
| description | Abstract Background Rehabilitative training is an effective method to promote recovery following spinal cord injury (SCI), with lower training efficacy observed in the chronic stage. The increased training efficacy during the subacute period is associated with a shift towards a more adaptive or proreparative state induced by the SCI. A potential link is SCI-induced inflammation, which is elevated in the subacute period, and, as injection of lipopolysaccharide (LPS) alongside training improves recovery in chronic SCI, suggesting LPS could reopen a window of plasticity late after injury. Microglia may play a role in LPS-mediated plasticity as they react to LPS and are implicated in facilitating recovery following SCI. However, it is unknown how microglia change in response to LPS following SCI to promote neuroplasticity. Main body Here we used single-cell RNA sequencing to examine microglial responses in subacute and chronic SCI with and without an LPS injection. We show that subacute SCI is characterized by a disease-associated microglial (DAM) signature, while chronic SCI is highly heterogeneous, with both injury-induced and homeostatic states. DAM states exhibit predicted metabolic pathway activity and neuronal interactions that are associated with potential mediators of plasticity. With LPS injection, microglia shifted away from the homeostatic signature to a primed, translation-associated state and increased DAM in degenerated tracts caudal to the injury. Conclusion Microglial states following an inflammatory stimulus in chronic injury incompletely recapitulate the subacute injury environment, showing both overlapping and distinct microglial signatures across time and with LPS injection. Our results contribute to an understanding of how microglia and LPS-induced neuroinflammation contribute to plasticity following SCI. |
| format | Article |
| id | doaj-art-c3d9c78cdbeb48718bb2b963d39c8688 |
| institution | OA Journals |
| issn | 1742-2094 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj-art-c3d9c78cdbeb48718bb2b963d39c86882025-08-20T02:16:45ZengBMCJournal of Neuroinflammation1742-20942025-02-0122111710.1186/s12974-025-03379-6Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial statesRebecca K. John0Sadie P. Vogel1Sameera Zia2Kelly V. Lee3Antoinette T. Nguyen4Abel Torres-Espin5Keith K. Fenrich6Carmen Ng7Emma K. A. Schmidt8Romana Vavrek9Pamela J. F. Raposo10Keira Smith11Karim Fouad12Jason R. Plemel13Neuroscience and Mental Health Institute, University of AlbertaNeuroscience and Mental Health Institute, University of AlbertaNeuroscience and Mental Health Institute, University of AlbertaDepartment of Medicine, Division of Neurology, University of AlbertaDepartment of Physical Therapy, Faculty of Rehabilitation Medicine, University of AlbertaDepartment of Physical Therapy, Faculty of Rehabilitation Medicine, University of AlbertaNeuroscience and Mental Health Institute, University of AlbertaNeuroscience and Mental Health Institute, University of AlbertaNeuroscience and Mental Health Institute, University of AlbertaDepartment of Physical Therapy, Faculty of Rehabilitation Medicine, University of AlbertaDepartment of Physical Therapy, Faculty of Rehabilitation Medicine, University of AlbertaNeuroscience and Mental Health Institute, University of AlbertaNeuroscience and Mental Health Institute, University of AlbertaNeuroscience and Mental Health Institute, University of AlbertaAbstract Background Rehabilitative training is an effective method to promote recovery following spinal cord injury (SCI), with lower training efficacy observed in the chronic stage. The increased training efficacy during the subacute period is associated with a shift towards a more adaptive or proreparative state induced by the SCI. A potential link is SCI-induced inflammation, which is elevated in the subacute period, and, as injection of lipopolysaccharide (LPS) alongside training improves recovery in chronic SCI, suggesting LPS could reopen a window of plasticity late after injury. Microglia may play a role in LPS-mediated plasticity as they react to LPS and are implicated in facilitating recovery following SCI. However, it is unknown how microglia change in response to LPS following SCI to promote neuroplasticity. Main body Here we used single-cell RNA sequencing to examine microglial responses in subacute and chronic SCI with and without an LPS injection. We show that subacute SCI is characterized by a disease-associated microglial (DAM) signature, while chronic SCI is highly heterogeneous, with both injury-induced and homeostatic states. DAM states exhibit predicted metabolic pathway activity and neuronal interactions that are associated with potential mediators of plasticity. With LPS injection, microglia shifted away from the homeostatic signature to a primed, translation-associated state and increased DAM in degenerated tracts caudal to the injury. Conclusion Microglial states following an inflammatory stimulus in chronic injury incompletely recapitulate the subacute injury environment, showing both overlapping and distinct microglial signatures across time and with LPS injection. Our results contribute to an understanding of how microglia and LPS-induced neuroinflammation contribute to plasticity following SCI.https://doi.org/10.1186/s12974-025-03379-6MicrogliaSpinal cord injuryInflammationSingle-cell RNA sequencingPlasticityLipopolysaccharide |
| spellingShingle | Rebecca K. John Sadie P. Vogel Sameera Zia Kelly V. Lee Antoinette T. Nguyen Abel Torres-Espin Keith K. Fenrich Carmen Ng Emma K. A. Schmidt Romana Vavrek Pamela J. F. Raposo Keira Smith Karim Fouad Jason R. Plemel Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states Journal of Neuroinflammation Microglia Spinal cord injury Inflammation Single-cell RNA sequencing Plasticity Lipopolysaccharide |
| title | Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states |
| title_full | Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states |
| title_fullStr | Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states |
| title_full_unstemmed | Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states |
| title_short | Reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states |
| title_sort | reawakening inflammation in the chronically injured spinal cord using lipopolysaccharide induces diverse microglial states |
| topic | Microglia Spinal cord injury Inflammation Single-cell RNA sequencing Plasticity Lipopolysaccharide |
| url | https://doi.org/10.1186/s12974-025-03379-6 |
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