RESUMO
Stroke is one of the leading causes of death and long-term disabilities worldwide. In addition to interruption of blood flow, inflammation is widely recognized as an important factor mediating tissue destruction in stroke. Depending on their phenotype, microglia, the main leukocytes in the CNS, are capable of either causing further tissue damage or promoting brain restoration after stroke. ß2-integrins are cell adhesion molecules that are constitutively expressed on microglia. The function of ß2-integrins has been investigated extensively in animal models of ischemic stroke, but their role in hemorrhagic stroke is currently poorly understood. We show in this study that dysfunction of ß2-integrins is associated with improved functional outcome and decreased inflammatory cytokine expression in the brain in a mouse model of hemorrhagic stroke. Furthermore, ß2-integrins affect microglial phenotype and cytokine responses in vivo. Therefore, our findings suggest that targeting ß2-integrins in hemorrhagic stroke may be beneficial.
Assuntos
Antígenos CD18 , Citocinas , Modelos Animais de Doenças , Acidente Vascular Cerebral Hemorrágico , Microglia , Animais , Microglia/imunologia , Microglia/metabolismo , Camundongos , Acidente Vascular Cerebral Hemorrágico/imunologia , Citocinas/metabolismo , Citocinas/imunologia , Antígenos CD18/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Masculino , Encéfalo/imunologia , Encéfalo/patologia , Encéfalo/metabolismo , Acidente Vascular Cerebral/imunologiaAssuntos
Interleucina-2 , AVC Isquêmico , Linfócitos T Reguladores , Animais , Humanos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/imunologia , Isquemia Encefálica/terapia , Interleucina-2/uso terapêutico , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/imunologia , AVC Isquêmico/terapia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/terapia , Linfócitos T Reguladores/imunologiaRESUMO
BACKGROUND: Stroke-Induced Immunodepression (SIID) is characterized by apoptosis in blood immune populations, such as T cells, B cells, NK cells, and monocytes, leading to the clinical presentation of lymphopenia. Disulfidptosis is a novel form of programmed cell death characterized by accumulating disulfide bonds in the cytoplasm, resulting in cellular dysfunction and eventual cell death. OBJECTIVE: In this study, we investigated the association between disulfidptosis and stroke by analyzing gene sequencing data from peripheral blood samples of stroke patients. METHODS: Differential gene expression analysis identified a set of disulfidptosis-related genes (DRGs) significantly associated with stroke. Initial exploration identified 32 DRGs and their interactions. Our study encompassed several analyses to understand the molecular mechanisms of DRGs in stroke. Weighted Gene Co-Expression Network Analysis (WGCNA) uncovered modules of co-expressed genes in stroke samples, and differentially expressed gene (DEG) analysis highlighted 1643 key genes. RESULTS: These analyses converged on four hub genes of DRGs (SLC2A3, SLC2A14, SLC7A11, NCKAP1) associated with stroke. Immune cell composition analysis indicated positive correlations between hub genes and macrophages M1, M2, and neutrophils and negative associations with CD4+ and CD8+ T cells, B cells, and NK cells. Sub-cluster analysis revealed two distinct clusters with different immune cell expression profiles. Gene Set Enrichment Analysis (GSEA) demonstrated enrichment of apoptosis-related pathways, neurotrophin signaling, and actin cytoskeleton regulation. Associations between hub genes and apoptosis, necroptosis, ferroptosis, and cuproptosis, were also identified. CONCLUSION: These results suggest that the DRG hub genes are interconnected with various cell death pathways and immune processes, potentially contributing to stroke pathological development.
Assuntos
Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/sangue , Apoptose/fisiologiaRESUMO
Cerebral stroke is ranked as the third most common contributor to global mortality and disability. The involvement of inflammatory mechanisms, both peripherally and within the CNS, holds significance in the pathophysiological cascades following the initiation of stroke. After the onset of acute stroke, predominantly ischemic, a subsequent phase of neuroinflammation ensues. It is a dual-effect process that not only exacerbates injury, leading to cell death, but paradoxically, it also serves a shielding role in facilitating recovery. Cytokines serve as pivotal mediators within the inflammatory cascade, actively contributing to the progression of ischemic damage. Stroke is followed by increased expression of pro-inflammatory cytokines including TNF-α, IL-1ß, IL-6, etc. leading to the recruitment and stimulation of glial cells and peripheral leukocytes at the site of injury, promoting neuroinflammation. Cytokines can directly induce neuronal injury and death through various mechanisms, including excitotoxicity, oxidative stress, HPA-axis activation, secretion of matrix metalloproteinase and apoptosis. They can also amplify the inflammatory response, leading to further neuronal damage. Therapeutic strategies aimed at modulating cytokine release, immune response and cytokine signalling or activity are being explored as potential interventions to mitigate neuroinflammation and its detrimental effects in stroke. In this review, we have given a concise summary of our current knowledge of the function of various cytokines, brain inflammation and various signalling and molecular pathways including JAK/STAT3, TGF-ß/Smad, MAPK, HMGB1/TLR and NF-κB modulated cytokines regulation in stroke. Therapeutic agents such as MCC950, genistein, edaravone, minocycline, etc. targeting various cytokines-associated signalling pathways have shown efficacy in preclinical and clinical trials reducing the pathophysiology of the illness were also addressed in this study.
Assuntos
Citocinas , Doenças Neuroinflamatórias , Acidente Vascular Cerebral , Humanos , Citocinas/imunologia , Animais , Acidente Vascular Cerebral/imunologia , Doenças Neuroinflamatórias/imunologia , Transdução de Sinais , Inflamação/imunologiaRESUMO
BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) and systemic inflammation response index (SIRI) at admission are independent diagnostic biomarkers in stroke-associated pneumonia (SAP). Our study aimed to investigate the association between NLR, SIRI, specifically follow-up NLR and SIRI, and SAP, as well as their relationship with functional outcomes. PATIENTS AND METHODS: We retrospectively included 451 consecutive intracerebral hemorrhage patients from May 2017 to May 2019. We conducted univariate and multivariable analyses to identify the factors independently associated with SAP and poor functional outcomes. RESULTS: Compared to 127 (28.16%) patients diagnosed with SAP, those without SAP had both lower baseline and follow-up NLR and SIRI values ( P <0.001). After adjustments, we found that baseline NLR [OR, 1.039 (95% CI, 1.003-1.077); P =0.036] and follow-up NLR [OR, 1.054 (95% CI, 1.011-1.098); P =0.012] were independently associated with SAP. The follow-up NLR was also associated with a higher mRS [OR, 1.124 (95% CI, 1.025-1.233); P =0.013] and lower ADL-MBI score [OR, 1.167 (95% CI, 1.057-1.289); P =0.002] at discharge. Multivariable analysis indicated that advanced age and nasogastric tube feeding were independently associated with SAP ( P <0.05). We constructed a dynamic nomogram to identify SAP risk. Further subgroup analysis revealed that baseline NLR [OR, 1.062 (95% CI, 1.007-1.120); P =0.026] is independently associated with SAP in the nasogastric feeding group, while follow-up NLR [OR, 1.080 (95% CI, 1.024-1.139); P =0.005] was associated with the occurrence of SAP in non-nasogastric feeding patients. CONCLUSIONS: We found elevated baseline and follow-up NLR values were associated with SAP occurrence, and increasing follow-up NLR indicated poor functional outcomes. Inflammatory markers at different stages may offer individualized guidance for patients receiving various treatments.
Assuntos
Hemorragia Cerebral , Linfócitos , Neutrófilos , Pneumonia , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Estudos Retrospectivos , Estudos de Casos e Controles , Hemorragia Cerebral/sangue , Pneumonia/sangue , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/imunologiaRESUMO
This review article discusses the potential of nanomaterials in targeted therapy and immunomodulation for stroke-induced immunosuppression. Although nanomaterials have been extensively studied in various biomedical applications, their specific use in studying and addressing immunosuppression after stroke remains limited. Stroke-induced neuroinflammation is characterized by T-cell-mediated immunodepression, which leads to increased morbidity and mortality. Key observations related to immunodepression after stroke, including lymphopenia, T-cell dysfunction, regulatory T-cell imbalance, and cytokine dysregulation, are discussed. Nanomaterials, such as liposomes, micelles, polymeric nanoparticles, and dendrimers, offer advantages in the precise delivery of drugs to T cells, enabling enhanced targeting and controlled release of immunomodulatory agents. These nanomaterials have the potential to modulate T-cell function, promote neuroregeneration, and restore immune responses, providing new avenues for stroke treatment. However, challenges related to biocompatibility, stability, scalability, and clinical translation need to be addressed. Future research efforts should focus on comprehensive studies to validate the efficacy and safety of nanomaterial-based interventions targeting T cells in stroke-induced immunosuppression. Collaborative interdisciplinary approaches are necessary to advance the field and translate these innovative strategies into clinical practice, ultimately improving stroke outcomes and patient care.
Assuntos
Nanoestruturas , Acidente Vascular Cerebral , Linfócitos T , Animais , Humanos , Citocinas/metabolismo , Citocinas/imunologia , Nanomedicina , Nanopartículas/química , Nanoestruturas/química , Acidente Vascular Cerebral/imunologia , Linfócitos T/imunologia , Linfócitos T/efeitos dos fármacosRESUMO
Post-stroke depression (PSD) is a psychological disease that can occur following a stroke and is associated with serious consequences. Research on the pathogenesis and treatment of PSD is still in the infancy stage. Patients with PSD often exhibit gastrointestinal symptoms; therefore the role of gut microbiota in the pathophysiology and potential treatment effects of PSD has become a hot topic of research. In this review, describe the research on the pathogenesis and therapy of PSD. We also describe how the gut microbiota influences neurotransmitters, the endocrine system, energy metabolism, and the immune system. It was proposed that the gut microbiota is involved in the pathogenesis and treatment of PSD through the regulation of neurotransmitter levels, vagal signaling, hypothalamic-pituitary-adrenal axis activation and inhibition, hormone secretion and release, in addition to immunity and inflammation.
Assuntos
Microbioma Gastrointestinal , Acidente Vascular Cerebral , Humanos , Microbioma Gastrointestinal/fisiologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/microbiologia , Depressão/microbiologia , Sistema Hipotálamo-Hipofisário/metabolismo , Animais , Sistema Hipófise-Suprarrenal/metabolismoRESUMO
Mounting evidence indicates that the immune response triggered by brain disorders (e.g., brain ischemia and autoimmune encephalomyelitis) occurs not only in the brain, but also in the skull. A key step toward analyzing changes in immune cell populations in both the brain and skull bone marrow after brain damage (e.g., stroke) is to obtain sufficient numbers of high-quality immune cells for downstream analyses. Here, two optimized protocols are provided for isolating immune cells from the brain and skull bone marrow. The advantages of both protocols are reflected in their simplicity, speed, and efficacy in yielding a large quantity of viable immune cells. These cells may be suitable for a range of downstream applications, such as cell sorting, flow cytometry, and transcriptomic analysis. To demonstrate the effectiveness of the protocols, immunophenotyping experiments were performed on stroke brains and normal brain skull bone marrow using flow cytometry analysis, and the results aligned with findings from published studies.
Assuntos
Encéfalo , Citometria de Fluxo , Crânio , Animais , Camundongos , Encéfalo/citologia , Encéfalo/imunologia , Crânio/citologia , Crânio/cirurgia , Citometria de Fluxo/métodos , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Acidente Vascular Cerebral/imunologia , Imunofenotipagem/métodosRESUMO
AIM: To explore the regulatory mechanisms of microglia-mediated cytotoxic CD8+ T-cell infiltration in the white matter injury of perioperative stroke (PIS). METHODS: Adult male C57BL/6 mice were subjected to ileocolic bowel resection (ICR) 24 h prior to permanent distant middle cerebral artery occlusion (dMCAO) to establish model PIS. White matter injury, functional outcomes, peripheral immune cell infiltration, and microglia phenotype were assessed up to 28 days after dMCAO using behavioral phenotyping, immunofluorescence staining, transmission electron microscopy, western blot, and FACS analysis. RESULTS: We found surgery aggravated white matter injury and deteriorated sensorimotor deficits up to 28 days following PIS. The PIS mice exhibited significantly increased activation of peripheral and central CD8+ T cells, while significantly reduced numbers of mature oligodendrocytes compared to IS mice. Neutralizing CD8+ T cells partly reversed the aggravated demyelination following PIS. Pharmacological blockage or genetic deletion of receptor-interacting protein kinase 1 (RIPK1) activity could alleviate CD8+ T-cell infiltration and demyelination in PIS mice. CONCLUSION: Surgery exacerbates demyelination and worsens neurological function by promoting infiltration of CD8+ T cells and microglia necroptosis, suggesting that modulating interactions of CD8+ T cells and microglia could be a novel therapeutic target of long-term neurological deficits of PIS.
Assuntos
Linfócitos T CD8-Positivos , Infarto da Artéria Cerebral Média , Camundongos Endogâmicos C57BL , Substância Branca , Animais , Masculino , Camundongos , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/imunologia , Substância Branca/patologia , Substância Branca/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/imunologia , Microglia/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Ativação Linfocitária , Modelos Animais de DoençasRESUMO
Following a stroke, an inflammatory response occurs, characterized by an increased blood-brain barrier permeability, expression of endothelial trafficking molecules, and infiltration of immune cells. Adhesion molecules expressed on activated brain endothelial cells are potential biomarkers of intraparenchymal inflammation. However, in current clinical practice, it is not possible to measure endothelial activation using clinically available imaging. Using targeted micro-sized particles of iron oxide (MPIO), immuno-MRI enables the detection of endothelial adhesion molecules at high resolution and, consequently, facilitates the detection of stroke-induced brain inflammation. In this review, we highlight the most recent studies that used immuno-MRI in models of neurovascular disorders, including transient ischemic attack, ischemic stroke, intracranial hemorrhage, and subarachnoid hemorrhage. We also discuss the potential of immuno-MRI in clinical practice and the necessary next steps for its implementation in patients.
Assuntos
Imageamento por Ressonância Magnética , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/imunologia , Imageamento por Ressonância Magnética/métodos , Animais , Prognóstico , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Encéfalo/diagnóstico por imagemRESUMO
Microglia represent the main immune cell population in the CNS with unique homeostatic roles and contribution to broad neurological conditions. Stroke is associated with marked changes in microglial phenotypes and induction of inflammatory responses, which emerge as key modulators of brain injury, neurological outcome and regeneration. However, due to the limited availability of functional studies with selective targeting of microglia and microglia-related inflammatory pathways in stroke, the vast majority of observations remain correlative and controversial. Because extensive review articles discussing the role of inflammatory mechanisms in different forms of acute brain injury are available, here we focus on some specific pathways that appear to be important for stroke pathophysiology with assumed contribution by microglia. While the growing toolkit for microglia manipulation increasingly allows targeting inflammatory pathways in a cell-specific manner, reconsideration of some effects devoted to microglia may also be required. This may particularly concern the interpretation of inflammatory mechanisms that emerge in response to stroke as a form of sterile injury and change markedly in chronic inflammation and common stroke comorbidities.
Assuntos
Inflamação , Microglia , Acidente Vascular Cerebral , Humanos , Microglia/metabolismo , Microglia/imunologia , Microglia/patologia , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/metabolismo , Animais , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Doenças Neuroinflamatórias/imunologia , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/metabolismoRESUMO
BACKGROUND: Ischemic stroke (IS) is a fearful disease that can cause a variety of immune events. Nevertheless, precise immune-related mechanisms have yet to be systematically elucidated. This study aimed to identify immune-related signatures using machine learning and to validate them with animal experiments and single cell analysis. METHODS: In this study, we screened 24 differentially expressed genes (DEGs) while identifying immune-related signatures that may play a key role in IS development through a comprehensive strategy between least absolute shrinkage and selection operation (LASSO) regression, support vector machine (SVM) and immune-related genes. In addition, we explored immune infiltration using the CIBERSORT algorithm. Finally, we performed validation in mouse brain tissue and single cell analysis. RESULTS: We identified 24 DEGs for follow-up analysis. ID3 and SLC22A4 were finally identified as the better immune-related signatures through a comprehensive strategy among DEGs, LASSO, SVM and immune-related genes. RT-qPCR, western blot, and immunofluorescence revealed a significant decrease in ID3 and a significant increase in SLC22A4 in the middle cerebral artery occlusion group. Single cell analysis revealed that ID3 was mainly concentrated in endothelial_2 cells and SLC22A4 in astrocytes in the MCAO group. A CIBERSORT finds significantly altered levels of immune infiltration in IS patients. CONCLUSIONS: This study focused on immune-related signatures after stroke and ID3 and SLC22A4 may be new therapeutic targets to promote functional recovery after stroke. Furthermore, the association of ID3 and SLC22A4 with immune cells may be a new direction for post-stroke immunotherapy.