RESUMEN
OBJECTIVES: Immune regulation is a pivotal factor in the pathogenesis and repair of spinal cord injury (SCI). This study aims to explore potential immune center genes associated with spinal cord injury. METHODS: The public data set GSE151371 was obtained from the GEO database. The R software package "limma" was used to identify differentially expressed genes (DEGs) in SCI. GO, KEGG and GSEA pathway analyses were performed using the DEGs. The key module genes related to spinal cord injury were selected through WGCNA analysis. Overlapping genes were extracted from WGCNA, DEGs, and immune-related genes. LASSO analysis was employed to identify central genes associated with SCI immunity. Pearson correlation analysis assessed the correlation between hub genes and immune cells in SCI. In addition, we further investigated the hub genes' expression, diagnostic potential, function, and targeted drugs. RESULTS: We have identified three immunity-related hub genes (ABHD5, EDNRB, EDN3). Immune infiltration analysis showed that the hub gene was significantly associated with resting NK cells, M2 macrophages, and monocytes in the immune microenvironment of SCI. ROC analysis demonstrated that these hub genes have favorable diagnostic performance for SCI. Functional analysis revealed that ABHD5 is primarily associated with lipid metabolism pathways, while EDN3 and EDNRB are mainly involved in endothelin, downstream GPCR signaling, and ERK signaling transduction. In addition, we identified six potential targeted drugs based on our findings. CONCLUSIONS: ABHD5, EDNRB, and EDN3 are involved in processes such as SCI progression or repair through immunomodulation and deserve further study.
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Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/inmunología , Humanos , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Biología Computacional/métodos , Mapas de Interacción de Proteínas/genéticaRESUMEN
The neurological deficits following traumatic spinal cord injury are associated with severe patient disability and economic consequences. Currently, an increasing number of studies are focusing on the importance of ferroptosis during acute organ injuries. However, the spatial and temporal distribution patterns of ferroptosis during SCI and the details of its role are largely unknown. In this study, in vivo experiments revealed that microglia are in close proximity to macrophages, the major cell type that undergoes ferroptosis following SCI. Furthermore, we found that ferroptotic macrophages aggravate SCI by inducing the proinflammatory properties of microglia. In vitro studies further revealed ferroptotic macrophages increased the expression of IL-1ß, IL-6, and IL-23 in microglia. Mechanistically, due to the activation of the NF-κB signaling pathway, the expression of IL-1ß and IL-6 was increased. In addition, we established that increased levels of oxidative phosphorylation cause mitochondrial reactive oxygen species generation and unfolded protein response activation and trigger an inflammatory response marked by an increase in IL-23 production. Our findings identified that targeting ferroptosis and IL-23 could be an effective strategy for promoting neurological recovery after SCI.
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Ferroptosis , Macrófagos , Microglía , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Microglía/inmunología , Microglía/metabolismo , Animales , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Especies Reactivas de Oxígeno/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Humanos , Interleucina-23/metabolismo , Modelos Animales de Enfermedad , MasculinoRESUMEN
Traumatic spinal cord injury (tSCI) is a severe injury to the central nervous system that is categorized into primary and secondary injuries. Among them, the local microenvironmental imbalance in the spinal cord caused by secondary spinal cord injury includes accumulation of cytokines and chemokines, reduced angiogenesis, dysregulation of cellular energy metabolism, and dysfunction of immune cells at the site of injury, which severely impedes neurological recovery from spinal cord injury (SCI). In recent years, single-cell techniques have revealed the heterogeneity of multiple immune cells at the genomic, transcriptomic, proteomic, and metabolomic levels after tSCI, further deepening our understanding of the mechanisms underlying tSCI. However, spatial information about the tSCI microenvironment, such as cell location and cell-cell interactions, is lost in these approaches. The application of spatial multi-omics technology can solve this problem by combining the data obtained from immunohistochemistry and multiparametric analysis to reveal the changes in the microenvironment at different times of secondary injury after SCI. In this review, we systematically review the progress of spatial multi-omics techniques in the study of the microenvironment after SCI, including changes in the immune microenvironment and discuss potential future therapeutic strategies.
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Microambiente Celular , Proteómica , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/metabolismo , Humanos , Microambiente Celular/inmunología , Proteómica/métodos , Animales , Metabolómica/métodos , Genómica/métodos , Transcriptoma , Análisis de la Célula Individual , MultiómicaRESUMEN
Neuropathic pain (NeP) is a type of persistent pain initiated by diseases or injuries of the nervous system. Although the underlying pathophysiological mechanisms of NeP are poorly understood, the immune system plays a key role in this condition. M2 macrophages have a key role in tissue healing and the reduction of inflammation. This systematic study aims to provide an overview of the role and importance of M2 macrophages in NeP after spinal cord injury (SCI). A comprehensive systematic review was conducted utilizing Scopus, PubMed, Embase, and ISI Web of Science databases. Two independent reviewers conducted the article selection. All publications examine the impact of M2 macrophages on NeP following spinal cord injuries. A quality assessment was conducted on bias entities that had been predetermined. Eleven papers met the criteria. According to the findings, focusing on immune cell polarization presents viable therapeutic options for treating NeP and enhancing recovery after SCI. M2 macrophages are essential for reducing neuropathic pain and promoting recovery after spinal cord injury. The modulation of M2 macrophages by a number of therapeutic approaches, including ivermectin-functionalized MWCNTs, isorhamnetin, Neuregulin-1 administration, TMEM16F inhibition, lentivirus-mediated delivery of anti-inflammatory cytokines, epigallocatechin-3-gallate, and red-light therapy promotes neuroregeneration, decreases neuroinflammatory cytokines, and reduces NeP. The results of these preclinical investigations must, however, be interpreted with caution, according to the quality assessment and risk of bias analysis of the studies that were included. Targeting M2 macrophages may have therapeutic benefits as they are essential for the management of NeP and recovery following spinal cord damage.
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Macrófagos , Neuralgia , Traumatismos de la Médula Espinal , Animales , Humanos , Macrófagos/inmunología , Neuralgia/inmunología , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/inmunologíaRESUMEN
Traumatic injuries to the central nervous system (CNS) afflict millions of individuals worldwide1, yet an effective treatment remains elusive. Following such injuries, the site is populated by a multitude of peripheral immune cells, including T cells, but a comprehensive understanding of the roles and antigen specificity of these endogenous T cells at the injury site has been lacking. This gap has impeded the development of immune-mediated cellular therapies for CNS injuries. Here, using single-cell RNA sequencing, we demonstrated the clonal expansion of mouse and human spinal cord injury-associated T cells and identified that CD4+ T cell clones in mice exhibit antigen specificity towards self-peptides of myelin and neuronal proteins. Leveraging mRNA-based T cell receptor (TCR) reconstitution, a strategy aimed to minimize potential adverse effects from prolonged activation of self-reactive T cells, we generated engineered transiently autoimmune T cells. These cells demonstrated notable neuroprotective efficacy in CNS injury models, in part by modulating myeloid cells via IFNγ. Our findings elucidate mechanistic insight underlying the neuroprotective function of injury-responsive T cells and pave the way for the future development of T cell therapies for CNS injuries.
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Autoinmunidad , Ingeniería Celular , Tratamiento Basado en Trasplante de Células y Tejidos , Sistema Nervioso Central , Neuroprotección , Traumatismos de la Médula Espinal , Linfocitos T , Animales , Femenino , Humanos , Masculino , Ratones , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/citología , Ingeniería Celular/métodos , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/lesiones , Células Clonales/citología , Células Clonales/inmunología , Modelos Animales de Enfermedad , Interferón gamma/inmunología , Ratones Endogámicos C57BL , Vaina de Mielina/inmunología , Células Mieloides/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/inmunología , Linfocitos T/inmunología , Linfocitos T/trasplante , Análisis de Expresión Génica de una Sola Célula , Proteínas del Tejido Nervioso/inmunologíaRESUMEN
Spinal cord injury (SCI) is a severe central nervous system disorder with no currently available effective treatment. Microglia are immune cells in the central nervous system that play crucial roles in the SCI occurrence, development, and recovery stages. They exhibit dynamic polarization over time and can switch between classical activation (M1) and alternative activation (M2) phenotypes to respond to environmental stimuli. The M1 phenotype is involved in initiating and sustaining inflammatory responses, while the M2 phenotype exerts anti-inflammatory effects and promotes tissue repair in damaged areas. Inhibiting M1 polarization and promoting M2 polarization have become hotspots in regulating neuroinflammation and treating SCI. This article provides a comprehensive review centered on modulating microglial polarization phenotypes for SCI treatment.
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Microglía , Fenotipo , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/inmunología , Microglía/fisiología , Microglía/metabolismo , Animales , Humanos , Enfermedades Neuroinflamatorias/inmunologíaRESUMEN
STUDY DESIGN: Experimental animal study. OBJECTIVES: To investigate the protective effect of remote limb ischemia preconditioning (RLPreC) on traumatic spinal cord injury (SCI) and explore the underlying biological mechanisms using RNA sequencing. SETTING: China Rehabilitation Science Institute; Beijing; China. METHODS: spinal cord injury was induced in mice using a force of 0.7 N. RLPreC treatment was administered. Motor function, pain behavior, and gene expression were assessed. RESULTS: RLPreC treatment significantly improved motor function and reduced pain-like behavior in SCI mice. RNA-Seq analysis identified 5247 differentially expressed genes (DEGs). GO analysis revealed enrichment of immune response, inflammatory signaling, and synaptic transmission pathways among these DEGs. KEGG analysis indicated suppression of inflammation and promotion of synapse-related pathways. CONCLUSIONS: RLPreC is a promising therapeutic strategy for improving motor function and alleviating pain after traumatic SCI. RNA-Seq analysis provides insights into potential therapeutic targets and warrants further investigation.
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Precondicionamiento Isquémico , Neuronas , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/inmunología , Precondicionamiento Isquémico/métodos , Ratones , Ratones Endogámicos C57BL , Masculino , Recuperación de la Función/fisiología , Supervivencia Celular/fisiología , Extremidades , Modelos Animales de Enfermedad , Inflamación/etiología , Actividad Motora/fisiología , Médula Espinal , Enfermedades Neuroinflamatorias/etiologíaRESUMEN
Aims: This paper was to scrutinize the toxicity mechanism of anti-programmed death 1 (anti-PD-1) therapy-caused spinal cord injury (SCI).Methods: Bone marrow transplant Rag1-/- mice were used to establish SCI model.Results: Anti-PD-1 results in SCI via CD8+ T-cells activation, while excessive activation of CD8+ T-cells further aggravated SCI. Both anti-PD-1 and the activation of CD8+ T-cells induced the expression of apoptosis-related perforin, GrB and FasL, but suppressed PI-9 level. The opposite results were observed in the effects of neuroserpin on these factors. CD8+ T-cells activation induced neurotoxicity via upregulation perforin, GrB and FasL and inhibiting PI-9. Additionally, neuroserpin suppressed CD8+ T-cells activation via perforin/GrB/PI-9/FasL pathways.Conclusion: These results may provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1.
What is this article about? In the process of treating cancer, immune checkpoint inhibitors such as anti-programmed death 1 (anti-PD-1) therapy, as a form of immunotherapy, have developed rapidly and changed the way to manage cancers significantly. However, some cancer patients who receive immune checkpoint blockade treatment suffer from severe adverse effects including spinal cord injury (SCI). This article for the first time constructed a bone marrow transplant mouse model to explore the toxicity mechanism of anti-PD-1 therapy-caused SCI.What were the results? We found that anti-PD-1 therapy can induce the activation of immune cells, while immune cell activation further promotes self-destruction of nerve cells by regulating cell death pathways.What do the results of the study mean? The mechanism of anti-PD-1 therapy-caused SCI is to activate of immune cells through regulating cell death pathways, thereby inducing self-destruction of nerve cells. These findings provide theoretical foundation for the clinical treatment of SCI caused by anti-PD-1 therapy.
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Trasplante de Médula Ósea , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Receptor de Muerte Celular Programada 1 , Traumatismos de la Médula Espinal , Animales , Ratones , Traumatismos de la Médula Espinal/inmunología , Ratones Noqueados , Linfocitos T CD8-positivos/inmunología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Humanos , Perforina/metabolismo , Proteína Ligando Fas/metabolismoRESUMEN
Spinal cord injury (SCI) is one of the most serious health problems, with no effective therapy. Recent studies indicate that Fisetin, a natural polyphenolic flavonoid, exhibits multiple functions, such as life-prolonging, antioxidant, antitumor, and neuroprotection. However, the restorative effects of Fisetin on SCI and the underlying mechanism are still unclear. In the present study, we found that Fisetin reduced LPS-induced apoptosis and oxidative damage in PC12 cells and reversed LPS-induced M1 polarization in BV2 cells. Additionally, Fisetin safely and effectively promoted the motor function recovery of SCI mice by attenuating neurological damage and promoting neurogenesis at the lesion. Moreover, Fisetin administration inhibited glial scar formation, modulated microglia/macrophage polarization, and reduced neuroinflammation. Network pharmacology, RNA-seq, and molecular biology revealed that Fisetin inhibited the activation of the JAK2/STAT3 signaling pathway. Notably, Colivelin TFA, an activator of JAK2/STAT3 signaling, attenuated Fis-mediated neuroinflammation inhibition and therapeutic effects on SCI mice. Collectively, Fisetin promotes functional recovery after SCI by inhibiting microglia/macrophage M1 polarization and the JAK2/STAT3 signaling pathway. Thus, Fisetin may be a promising therapeutic drug for the treatment of SCI.
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Flavonoles , Janus Quinasa 2 , Macrófagos , Microglía , Factor de Transcripción STAT3 , Transducción de Señal , Traumatismos de la Médula Espinal , Animales , Humanos , Masculino , Ratones , Ratas , Polaridad Celular/efectos de los fármacos , Flavonoides/farmacología , Flavonoides/administración & dosificación , Flavonoles/farmacología , Janus Quinasa 2/metabolismo , Janus Quinasa 2/genética , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/inmunología , Células PC12 , Recuperación de la Función/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/genética , Traumatismos de la Médula Espinal/fisiopatología , Traumatismos de la Médula Espinal/inmunología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genéticaRESUMEN
Spinal cord injury (SCI) represents a highly debilitating trauma to the central nervous system, currently lacking effective therapeutic strategies. The cascade of inflammatory responses induced by secondary damage following SCI disrupts the local immune environment at the injury site, ultimately exacerbating functional impairments post-injury. With advancing research on the gut-brain axis, evidence suggests that dysbiosis of the gut microbiota post-SCI amplifies inflammatory responses and plays a pivotal role in modulating post-injury immune-inflammatory responses. In this review article, we will explore the significant role of the gut microbiota and its metabolic products in modulating the responses of central and peripheral immune cells post-SCI, as well as their potential as therapeutic interventions for SCI treatment.
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Inmunidad Adaptativa , Microbioma Gastrointestinal , Inmunidad Innata , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/microbiología , Microbioma Gastrointestinal/inmunología , Microbioma Gastrointestinal/fisiología , Humanos , Animales , Inmunidad Adaptativa/inmunología , Eje Cerebro-Intestino/fisiología , Disbiosis/inmunologíaRESUMEN
Spinal cord injury triggers a strong innate inflammatory response in both non-regenerative mammals and regenerative zebrafish. Neutrophils are the first immune population to be recruited to the injury site. Yet, their role in the repair process, particularly in a regenerative context, remains largely unknown. Here, we show that, following rapid recruitment to the injured spinal cord, neutrophils mostly reverse migrate throughout the zebrafish body. In addition, promoting neutrophil inflammation resolution by inhibiting Cxcr4 boosts cellular and functional regeneration. Neutrophil-specific RNA-seq analysis reveals an enhanced activation state that correlates with a transient increase in tnf-α expression in macrophage/microglia populations. Conversely, blocking neutrophil recruitment through Cxcr1/2 inhibition diminishes the presence of macrophage/microglia at the injury site and impairs spinal cord regeneration. Altogether, these findings provide new insights into the role of neutrophils in spinal cord regeneration, emphasizing the significant impact of their immune profile on the outcome of the repair process.
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Neutrófilos , Traumatismos de la Médula Espinal , Regeneración de la Medula Espinal , Médula Espinal , Pez Cebra , Animales , Neutrófilos/metabolismo , Neutrófilos/inmunología , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/metabolismo , Regeneración de la Medula Espinal/fisiología , Médula Espinal/inmunología , Médula Espinal/metabolismo , Macrófagos/metabolismo , Macrófagos/inmunología , Microglía/metabolismo , Microglía/inmunología , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Receptores CXCR4/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Infiltración Neutrófila/fisiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Blood always shows coagulation changes after spinal cord injury (SCI), and identifying these blood changes may be helpful for diagnosis and treatment of SCI. Nevertheless, studies to date on blood coagulation changes after SCI in humans are not comprehensive. Therefore, this study aims to identify blood coagulation diagnostic biomarkers and immune changes related to SCI and its severity levels. METHODS: Human blood sequencing datasets were obtained from public databases. Differentially expressed coagulation-related genes were analyzed (DECRGs). Enrichment analysis and assessment of immune changes were conducted. Weighted gene co-expression network analysis, least absolute shrinkage and selection operator logistic regression were used to identify biomarkers. Validation for these biomarkers was performed. The correlation between biomarkers and immune cells was evaluated. Transcription factors, miRNA, lncRNA, and drugs that can regulate biomarkers were analyzed. RESULTS: DECRGs associated with SCI and its different grades were identified, showing enrichment in altered coagulation and immune-related signaling pathways. ADAM9, CD55, and STAT4 were identified as coagulation diagnostic biomarkers for SCI. IRF4 and PABPC4 were identified as coagulation diagnostic biomarkers for American Spinal Injury Association Impairment Scale (AIS) A grade of SCI. GP9 was designated as a diagnostic biomarker for AIS D grade of SCI. Immune changes in blood of SCI and its different grades were observed. Correlation between diagnostic biomarkers and immune cells were identified. Transcription factors, miRNA, lncRNA, and drugs that can regulate diagnostic biomarker expression were discovered. CONCLUSION: Therefore, detecting the expression of these putative diagnostic biomarkers and related immune changes may be helpful for predicting the severity of SCI. Uncovering potential regulatory mechanisms for biomarkers may be beneficial for further research.
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Biomarcadores , Coagulación Sanguínea , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/sangre , Traumatismos de la Médula Espinal/diagnóstico , Traumatismos de la Médula Espinal/inmunología , Biomarcadores/sangre , Índice de Severidad de la Enfermedad , MicroARNs/sangre , MicroARNs/genética , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismoRESUMEN
BACKGROUND: Traumatic brain injury (TBI) and spinal cord injury (SCI) are acquired injuries to the central nervous system (CNS) caused by external forces that cause temporary or permanent sensory and motor impairments and the potential for long-term disability or even death. These conditions currently lack effective treatments and impose substantial physical, social, and economic burdens on millions of people and families worldwide. TBI and SCI involve intricate pathological mechanisms, and the inflammatory response contributes significantly to secondary injury in TBI and SCI. It plays a crucial role in prolonging the post-CNS trauma period and becomes a focal point for a potential therapeutic intervention. Previous research on the inflammatory response has traditionally concentrated on glial cells, such as astrocytes and microglia. However, increasing evidence highlights the crucial involvement of lymphocytes in the inflammatory response to CNS injury, particularly CD8+ T cells and NK cells, along with their downstream XCL1-XCR1 axis. OBJECTIVE: This review aims to provide an overview of the role of the XCL1-XCR1 axis and the T-cell response in inflammation caused by TBI and SCI and identify potential targets for therapy. METHODS: We conducted a comprehensive search of PubMed and Web of Science using relevant keywords related to the XCL1-XCR1 axis, T-cell response, TBI, and SCI. RESULTS: This study examines the upstream and downstream pathways involved in inflammation caused by TBI and SCI, including interleukin-15 (IL-15), interleukin-12 (IL-12), CD8+ T cells, CD4+ T cells, NK cells, XCL1, XCR1+ dendritic cells, interferon-gamma (IFN-γ), helper T0 cells (Th0 cells), helper T1 cells (Th1 cells), and helper T17 cells (Th17 cells). We describe their proinflammatory effect in TBI and SCI. CONCLUSIONS: The findings suggest that the XCL1-XCR1 axis and the T-cell response have great potential for preclinical investigations and treatments for TBI and SCI.
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Lesiones Traumáticas del Encéfalo , Quimiocinas C , Traumatismos de la Médula Espinal , Humanos , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/patología , Lesiones Traumáticas del Encéfalo/inmunología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/metabolismo , Lesiones Traumáticas del Encéfalo/patología , Animales , Quimiocinas C/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Enfermedades Neuroinflamatorias/inmunologíaRESUMEN
Objective: Immunoregulation is a complex and critical process in the pathological process of spinal cord injury (SCI), which is regulated by various factors and plays an important role in the functional repair of SCI. This study aimed to explore the research hotspots and trends of glial cell immunoregulation after SCI from a bibliometric perspective. Methods: Data on publications related to glial cell immunoregulation after SCI, published from 2004 to 2023, were obtained from the Web of Science Core Collection. Countries, institutions, authors, journals, and keywords in the topic were quantitatively analyzed using the R package "bibliometrix", VOSviewer, Citespace, and the Bibliometrics Online Analysis Platform. Results: A total of 613 papers were included, with an average annual growth rate of 9.39%. The papers came from 36 countries, with the United States having the highest output, initiating collaborations with 27 countries. Nantong University was the most influential institution. We identified 3,177 authors, of whom Schwartz, m, of the Weizmann Institute of Science, was ranked first regarding both field-specific H-index (18) and average number of citations per document (151.44). Glia ranked first among journals with 2,574 total citations. The keywords "microglia," "activation," "macrophages," "astrocytes," and "neuroinflammation" represented recent hot topics and are expected to remain a focus of future research. Conclusion: These findings strongly suggest that the immunomodulatory effects of microglia, astrocytes, and glial cell interactions may be critical in promoting nerve regeneration and repair after SCI. Research on the immunoregulation of glial cells after SCI is emerging, and there should be greater cooperation and communication between countries and institutions to promote the development of this field and benefit more SCI patients.
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Bibliometría , Neuroglía , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/inmunología , Humanos , Neuroglía/inmunología , Animales , Astrocitos/inmunologíaRESUMEN
Spinal cord injury (SCI) is a severe neurological condition that frequently leads to significant sensory, motor, and autonomic dysfunction. This study sought to delineate the potential mechanistic underpinnings of extracellular vesicles (EVs) derived from ginsenoside Rg1-pretreated neuronal cells (Rg1-EVs) in ameliorating SCI. These results demonstrated that treatment with Rg1-EVs substantially improved motor function in spinal cord-injured mice. Rg1-EVs enhance microglial polarization toward the M2 phenotype and repressed oxidative stress, thereby altering immune responses and decreasing inflammatory cytokine secretion. Moreover, Rg1-EVs substantially diminish reactive oxygen species accumulation and enhanced neural tissue repair by regulating mitochondrial function. Proteomic profiling highlighted a significant enrichment of MYCBP2 in Rg1-EVs, and functional assays confirmed that MYCBP2 knockdown counteracted the beneficial effects of Rg1-EVs in vitro and in vivo. Mechanistically, MYCBP2 is implicated in the ubiquitination and degradation of S100A9, thereby promoting microglial M2-phenotype polarization and reducing oxidative stress. Overall, these findings substantiated the pivotal role of Rg1-EVs in neuronal protection and functional recovery following SCI through MYCBP2-mediated ubiquitination of S100A9. This research offers novel mechanistic insights into therapeutic strategies against SCI and supports the clinical potential of Rg1-EVs.
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Modelos Animales de Enfermedad , Vesículas Extracelulares , Ginsenósidos , Neuronas , Recuperación de la Función , Traumatismos de la Médula Espinal , Animales , Ginsenósidos/farmacología , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/efectos de los fármacos , Ratones , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/tratamiento farmacológico , Traumatismos de la Médula Espinal/inmunología , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Recuperación de la Función/efectos de los fármacos , Ratones Endogámicos C57BL , Microglía/efectos de los fármacos , Microglía/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
Spinal cord injury (SCI) resulting from trauma decreases the quality of human life. Numerous clues indicate that the limited endogenous regenerative potential is a result of the interplay between the inhibitory nature of mature nervous tissue and the inflammatory actions of immune and glial cells. Knowledge gained from comparing regeneration in adult and juvenile animals could draw attention to factors that should be removed or added for effective therapy in adults. Therefore, we generated a minimal SCI (mSCI) model with a comparable impact on the spinal cord of Wistar rats during adulthood, preadolescence, and the neonatal period. The mechanism of injury is based on unilateral incision with a 20 ga needle tip according to stereotaxic coordinates into the dorsal horn of the L4 lumbar spinal segment. The incision should harm a similar amount of gray matter on a coronal section in each group of experimental animals. According to our results, the impact causes mild injury with minimal adverse effects on the neurological functions of animals but still has a remarkable effect on nervous tissue and its cellular and humoral components. Testing the mSCI model in adults, preadolescents, and neonates revealed a rather anti-inflammatory response of immune cells and astrocytes at the lesion site, as well as increased proliferation in the central canal lining in neonates compared with adult animals. Our results indicate that developing nervous tissue could possess superior reparative potential and confirm the importance of comparative studies to advance in the field of neuroregeneration.
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Animales Recién Nacidos , Proliferación Celular , Modelos Animales de Enfermedad , Ratas Wistar , Traumatismos de la Médula Espinal , Animales , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/patología , Traumatismos de la Médula Espinal/fisiopatología , Proliferación Celular/fisiología , Ratas , Médula Espinal/patología , Médula Espinal/inmunología , Astrocitos/patología , FemeninoRESUMEN
The adult central nervous system (CNS) possesses a limited capacity for self-repair. Severed CNS axons typically fail to regrow. There is an unmet need for treatments designed to enhance neuronal viability, facilitate axon regeneration and ultimately restore lost neurological functions to individuals affected by traumatic CNS injury, multiple sclerosis, stroke and other neurological disorders. Here we demonstrate that both mouse and human bone marrow neutrophils, when polarized with a combination of recombinant interleukin-4 (IL-4) and granulocyte colony-stimulating factor (G-CSF), upregulate alternative activation markers and produce an array of growth factors, thereby gaining the capacity to promote neurite outgrowth. Moreover, adoptive transfer of IL-4/G-CSF-polarized bone marrow neutrophils into experimental models of CNS injury triggered substantial axon regeneration within the optic nerve and spinal cord. These findings have far-reaching implications for the future development of autologous myeloid cell-based therapies that may bring us closer to effective solutions for reversing CNS damage.
Asunto(s)
Axones , Factor Estimulante de Colonias de Granulocitos , Interleucina-4 , Ratones Endogámicos C57BL , Regeneración Nerviosa , Neutrófilos , Animales , Neutrófilos/inmunología , Regeneración Nerviosa/inmunología , Ratones , Humanos , Axones/metabolismo , Axones/fisiología , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos/farmacología , Interleucina-4/metabolismo , Activación Neutrófila , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/metabolismo , Traslado Adoptivo , Citocinas/metabolismo , Células CultivadasRESUMEN
Developing biomimetic nanoparticles without off-target side-effects remains a major challenge in spinal cord injury (SCI) immunotherapy. In this paper, we have conducted a drug carrier which is biocompatible macrophages-exocytosed exosome-biomimetic manganese (Mn)-iron prussian blue analogues (MPBs) for SCI immunotherapy. Exosome-sheathed MPBs (E-MPBs) exhibit promoted microglia accumulation, alleviation from H2O2-induced microenvironment and inhibition of apoptosis and inflammation in vitro. In addition, E-MPBs possessed significant tissue repair and neuroprotection in vivo. These properties endowed E-MPBs with great improvement in vivo in function recovery, resulting in anti-neuroinflammation activity and excellent biocompatibility in mice SCI model. As a promising treatment for efficient SCI immunotherapy, these results demonstrate the use of exosome-sheathed biomimetic nanoparticles exocytosed by anti-inflammation cells is feasible.
Asunto(s)
Exosomas , Inmunoterapia , Macrófagos , Nanopartículas , Traumatismos de la Médula Espinal , Animales , Exosomas/trasplante , Exosomas/metabolismo , Traumatismos de la Médula Espinal/terapia , Traumatismos de la Médula Espinal/inmunología , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Ratones , Nanopartículas/química , Inmunoterapia/métodos , Ferrocianuros/química , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Humanos , Microglía/inmunología , Células RAW 264.7 , Apoptosis/efectos de los fármacosRESUMEN
Spinal Cord Injury (SCI) disrupts critical autonomic pathways responsible for the regulation of the immune function. Consequently, individuals with SCI often exhibit a spectrum of immune dysfunctions ranging from the development of damaging pro-inflammatory responses to severe immunosuppression. Thus, it is imperative to gain a more comprehensive understanding of the extent and mechanisms through which SCI-induced autonomic dysfunction influences the immune response. In this review, we provide an overview of the anatomical organization and physiology of the autonomic nervous system (ANS), elucidating how SCI impacts its function, with a particular focus on lymphoid organs and immune activity. We highlight recent advances in understanding how intraspinal plasticity that follows SCI may contribute to aberrant autonomic activity in lymphoid organs. Additionally, we discuss how sympathetic mediators released by these neuron terminals affect immune cell function. Finally, we discuss emerging innovative technologies and potential clinical interventions targeting the ANS as a strategy to restore the normal regulation of the immune response in individuals with SCI.
Asunto(s)
Vías Autónomas , Traumatismos de la Médula Espinal , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/fisiopatología , Humanos , Animales , Vías Autónomas/inmunología , Sistema Nervioso Autónomo/fisiopatología , Sistema Nervioso Autónomo/inmunologíaRESUMEN
BACKGROUND: Spinal cord injury (SCI) is a traumatic neurological disorder with limited therapeutic options. Tumor protein p53-inducible nuclear protein 2 (TP53INP2) is involved in the occurrence and development of various diseases, and it may play a role during SCI via affecting inflammation and neuronal apoptosis. This study investigated the associated roles and mechanisms of TP53INP2 in SCI. METHODS: Mouse and lipopolysaccharide (LPS)-induced SCI BV-2 cell models were constructed to explore the role of TP53INP2 in SCI and the associated mechanisms. Histopathological evaluation of spinal cord tissue was detected by hematoxylin and eosin staining. The Basso, Beattie, and Bresnahan score was used to measure the motor function of the mice, while the spinal cord water content was used to assess spinal cord edema. The expression of TP53INP2 was measured using RT-qPCR. In addition, inflammatory factors in the spinal cord tissue of SCI mice and LPS-treated BV-2 cells were measured using enzyme-linked immunosorbent assay. Apoptosis and related protein expression levels were detected by flow cytometry and western blot analysis, respectively. RESULTS: TP53INP2 levels increased in SCI mice and LPS-treated BV-2 cells. The results of in vivo and in vitro experiments showed that TP53INP2 knockdown inhibited the inflammatory response and neuronal apoptosis in mouse spinal cord tissue or LPS-induced BV-2 cells. CONCLUSIONS: After spinal cord injury, TP53INP2 was upregulated, and TP53INP2 knockdown inhibited the inflammatory response and apoptosis.