Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury
Abstract Background Spinal cord injury (SCI) triggers a complex inflammatory response that impedes neural repair and functional recovery. The modulation of macrophage phenotypes is thus considered a promising therapeutic strategy to mitigate inflammation and promote regeneration. Methods We employed...
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BMC
2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-024-05916-y |
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| author | Shijie Yang Beibei Yu Qing Zhang Yongfeng Zhang Longhui Fu Bisheng Zhou Haining Wu Jianzhong Li Shouping Gong |
| author_facet | Shijie Yang Beibei Yu Qing Zhang Yongfeng Zhang Longhui Fu Bisheng Zhou Haining Wu Jianzhong Li Shouping Gong |
| author_sort | Shijie Yang |
| collection | DOAJ |
| description | Abstract Background Spinal cord injury (SCI) triggers a complex inflammatory response that impedes neural repair and functional recovery. The modulation of macrophage phenotypes is thus considered a promising therapeutic strategy to mitigate inflammation and promote regeneration. Methods We employed microarray and single-cell RNA sequencing (scRNA-seq) to investigate gene expression changes and immune cell dynamics in mice following crush injury at 3 and 7 days post-injury (dpi). High-dimensional gene co-expression network analysis (hdWGCNA) and slingshot trajectory analysis were employed to identify key gene modules and macrophage differentiation pathways. Subsequently, immunofluorescence staining, flow cytometry, and western blotting were performed to validate the identified effects of amantadine on macrophage differentiation and inflammation. Results To elucidate the molecular mechanisms underlying the injury response at the transcriptional level, we performed a microarray analysis followed by gene set enrichment analysis (GSEA). The results revealed that pathways related to phagocytosis and macrophage activation are significantly involved post-injury, shedding light on the regulatory role of macrophages in SCI repair. To further investigate macrophage dynamics within the injured spinal cord, we conducted scRNA-Seq, identifying three distinct macrophage subtypes: border-associated macrophages (BAMs), inflammatory macrophages (IMs), and chemotaxis-inducing macrophages (CIMs). Trajectory analysis suggested a differentiation pathway from Il-1b+ IMs to Mrc1+ BAMs, and subsequently to Arg1+ CIMs, indicating a potential maturation process. Given the importance of these pathways in the injury response, we utilized molecular docking to hypothesize that amantadine might modulate this process. Subsequent in vitro and in vivo experiments demonstrated that amantadine reduces Il-1b+ IMs and facilitates the transition to Mrc1+ BAMs and Arg1+ CIMs, likely through modulation of the HIF-1α and NF-κB pathways. This modulation promotes neural regeneration and enhances functional recovery following SCI. Conclusions Amantadine modulates macrophage phenotypes following SCI, reduces early inflammatory responses, and enhances neural function recovery. These findings highlight the therapeutic potential of amantadine as a treatment for SCI, and provide a foundation for future translational research into its clinical applications. |
| format | Article |
| id | doaj-art-4441df6e1ab7428e8b20d4afd6b22bf1 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-4441df6e1ab7428e8b20d4afd6b22bf12025-01-19T12:37:07ZengBMCJournal of Translational Medicine1479-58762025-01-0123111910.1186/s12967-024-05916-yAmantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injuryShijie Yang0Beibei Yu1Qing Zhang2Yongfeng Zhang3Longhui Fu4Bisheng Zhou5Haining Wu6Jianzhong Li7Shouping Gong8Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Jiao Tong UniversityDepartment of Neurosurgery, The Second Affiliated Hospital of Xi’an Jiao Tong UniversityKey Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi’an Jiaotong UniversityDepartment of Neurosurgery, The Second Affiliated Hospital of Xi’an Jiao Tong UniversityDepartment of Neurosurgery, The Second Affiliated Hospital of Xi’an Jiao Tong UniversityDepartment of Neurosurgery, The Second Affiliated Hospital of Xi’an Jiao Tong UniversityDepartment of Orthopaedics, Xijing Hospital, Fourth Military Medical UniversityDepartment of Thoracic Surgery, Second Affiliated Hospital of Xi’an Jiao Tong UniversityDepartment of Neurosurgery, The Second Affiliated Hospital of Xi’an Jiao Tong UniversityAbstract Background Spinal cord injury (SCI) triggers a complex inflammatory response that impedes neural repair and functional recovery. The modulation of macrophage phenotypes is thus considered a promising therapeutic strategy to mitigate inflammation and promote regeneration. Methods We employed microarray and single-cell RNA sequencing (scRNA-seq) to investigate gene expression changes and immune cell dynamics in mice following crush injury at 3 and 7 days post-injury (dpi). High-dimensional gene co-expression network analysis (hdWGCNA) and slingshot trajectory analysis were employed to identify key gene modules and macrophage differentiation pathways. Subsequently, immunofluorescence staining, flow cytometry, and western blotting were performed to validate the identified effects of amantadine on macrophage differentiation and inflammation. Results To elucidate the molecular mechanisms underlying the injury response at the transcriptional level, we performed a microarray analysis followed by gene set enrichment analysis (GSEA). The results revealed that pathways related to phagocytosis and macrophage activation are significantly involved post-injury, shedding light on the regulatory role of macrophages in SCI repair. To further investigate macrophage dynamics within the injured spinal cord, we conducted scRNA-Seq, identifying three distinct macrophage subtypes: border-associated macrophages (BAMs), inflammatory macrophages (IMs), and chemotaxis-inducing macrophages (CIMs). Trajectory analysis suggested a differentiation pathway from Il-1b+ IMs to Mrc1+ BAMs, and subsequently to Arg1+ CIMs, indicating a potential maturation process. Given the importance of these pathways in the injury response, we utilized molecular docking to hypothesize that amantadine might modulate this process. Subsequent in vitro and in vivo experiments demonstrated that amantadine reduces Il-1b+ IMs and facilitates the transition to Mrc1+ BAMs and Arg1+ CIMs, likely through modulation of the HIF-1α and NF-κB pathways. This modulation promotes neural regeneration and enhances functional recovery following SCI. Conclusions Amantadine modulates macrophage phenotypes following SCI, reduces early inflammatory responses, and enhances neural function recovery. These findings highlight the therapeutic potential of amantadine as a treatment for SCI, and provide a foundation for future translational research into its clinical applications.https://doi.org/10.1186/s12967-024-05916-ySpinal cord injury (SCI)scRNA-seqhdWGCNAAmantadineMacrophage |
| spellingShingle | Shijie Yang Beibei Yu Qing Zhang Yongfeng Zhang Longhui Fu Bisheng Zhou Haining Wu Jianzhong Li Shouping Gong Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury Journal of Translational Medicine Spinal cord injury (SCI) scRNA-seq hdWGCNA Amantadine Macrophage |
| title | Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury |
| title_full | Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury |
| title_fullStr | Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury |
| title_full_unstemmed | Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury |
| title_short | Amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury |
| title_sort | amantadine modulates novel macrophage phenotypes to enhance neural repair following spinal cord injury |
| topic | Spinal cord injury (SCI) scRNA-seq hdWGCNA Amantadine Macrophage |
| url | https://doi.org/10.1186/s12967-024-05916-y |
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