Cytokines in CAR T Cell–Associated Neurotoxicity

Frontiers in Immunology, Год журнала: 2020, Номер 11

Опубликована: Дек. 16, 2020

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium language dysfunction to seizures, coma, fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated (ICANS). In this review, we draw an arc our current understanding how systemic local cytokine release act on the CNS, toward possible preventive approaches. We systematically review reported correlations secreted inflammatory mediators in serum/plasma cerebrospinal fluid risk ICANS receiving CAR cell therapy. Possible pathophysiologic impacts CNS are covered detail most promising candidate cytokines, including IL-1, IL-6, IL-15, GM-CSF. To insight into final common pathways inflammation, place context other conditions that associated neurologic dysfunction, sepsis-associated encephalopathy, malaria, thrombotic microangiopathy, infections, hepatic encephalopathy. then what known about interaction components neurovascular unit, endothelial cells, pericytes, astrocytes, microglia neurons respond challenges. Current approaches, corticosteroids blockade IL-1 IL-6 signaling, reviewed role cytokines ICANS. Throughout, point out gaps knowledge approaches investigation mechanism, prevention, treatment

Язык: Английский

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The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis

Glia, Год журнала: 2022, Номер 70(7), С. 1215 - 1250

Опубликована: Фев. 2, 2022

Abstract In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site by microglia is critically important to achieve adequate slow progression disease. However, how phagocytose debris, why impaired in MS, not fully known; likewise, role remains unclear. Recent studies using cuprizone (CPZ) animal model central nervous system revealed that up‐regulation signaling proteins facilitates effective phagocytosis debris. Moreover, during demyelination, protective mediators are released activated microglia, resulting acceleration CPZ model. contrast, inadequate microglial activation or recruitment production toxic mediators, impairs demyelination. addition microglia‐mediated phagocytosis, astrocytes play phagocytic process recruiting producing regenerative mediators. current review update these emerging findings model, discussing roles myelination.

Язык: Английский

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Analysis of brain and blood single-cell transcriptomics in acute and subacute phases after experimental stroke

Nature Immunology, Год журнала: 2024, Номер 25(2), С. 357 - 370

Опубликована: Янв. 4, 2024

Язык: Английский

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Single-cell sequencing reveals the landscape of the human brain metastatic microenvironment

Communications Biology, Год журнала: 2023, Номер 6(1)

Опубликована: Июль 21, 2023

Abstract Brain metastases is the most common intracranial tumor and account for approximately 20% of all systematic cancer cases. It a leading cause death in advanced-stage cancer, resulting five-year overall survival rate below 10%. Therefore, there critical need to identify effective biomarkers that can support frequent surveillance promote efficient drug guidance brain metastasis. Recently, remarkable breakthroughs single-cell RNA-sequencing (scRNA-seq) technology have advanced our insights into microenvironment (TME) at resolution, which offers potential unravel metastasis-related cellular crosstalk provides improving therapeutic effects mediated by multifaceted interactions within TME. In this study, we applied scRNA-seq profiled 10,896 cells collected from five tissue samples originating breast lung cancers. Our analysis reveals presence various intratumoral components, including cells, fibroblasts, myeloid stromal expressing neural stem cell markers, as well minor populations oligodendrocytes T cells. Interestingly, distinct compositions are observed across different samples, indicating influence diverse on infiltration patterns Importantly, tumor-associated fibroblasts both in-house dataset external datasets. These exhibit high expression type I collagen genes, dominate cell-cell TME via signaling axis, facilitate remodeling collagen-I-rich extracellular matrix similar original primary sites. Additionally, observe M1 activation native microglial infiltrated macrophages, may contribute proinflammatory upregulation fibroblasts. Furthermore, cell-specific receptors significant association with patient metastasis glioblastoma Taken together, comprehensive analyses collagen-secreting key mediators metastatic tumors uncover potentially associated survival. discoveries provide targets intervention strategies.

Язык: Английский

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Microglial expression of CD83 governs cellular activation and restrains neuroinflammation in experimental autoimmune encephalomyelitis

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Авг. 1, 2023

Abstract Microglial activation during neuroinflammation is crucial for coordinating the immune response against neuronal tissue, and initial of microglia determines severity neuro-inflammatory diseases. The CD83 molecule has been recently shown to modulate status dendritic cells macrophages. Although expression associated with early in various disease settings, its functional relevance microglial biology elusive. Here, we describe a thorough assessment regulation show that murine not only cellular but also pro-resolving functions. Using single-cell RNA-sequencing, reveal conditional deletion results an over-activated state experimental autoimmune encephalomyelitis model. Subsequently, CD83-deficient recruit more pathogenic central nervous system, deteriorating resolving mechanisms exacerbating disease. Thus, orchestrates and, consequently, resolution neuroinflammation.

Язык: Английский

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Cellular senescence in brain aging and cognitive decline

Frontiers in Aging Neuroscience, Год журнала: 2023, Номер 15

Опубликована: Ноя. 23, 2023

Cellular senescence is a biological aging hallmark that plays key role in the development of neurodegenerative diseases. Clinical trials are currently underway to evaluate effectiveness senotherapies for these However, impact on brain and cognitive decline absence neurodegeneration remains uncertain. Moreover, patient populations like cancer survivors, traumatic injury obese individuals, obstructive sleep apnea patients, chronic kidney disease patients can suffer age-related changes prematurely, suggesting they may accelerated brain. Understanding neurocognitive deficits linked conditions crucial, especially considering rapidly evolving field senotherapeutics. Such treatments could help alleviate early significantly reducing morbidity healthcare costs. This review provides translational perspective how cellular decline. We also discuss important caveats surrounding mainstream senolytics senomorphics, present emerging evidence hyperbaric oxygen therapy immune-directed therapies as viable modalities senescent cell burden.

Язык: Английский

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Single-Cell RNA-Sequencing: Astrocyte and Microglial Heterogeneity in Health and Disease

Cells, Год журнала: 2022, Номер 11(13), С. 2021 - 2021

Опубликована: Июнь 24, 2022

Astrocytes and microglia are non-neuronal cells that maintain homeostasis within the central nervous system via their capacity to regulate neuronal transmission prune synapses. Both astrocytes can undergo morphological transcriptomic changes in response infection with human immunodeficiency virus (HIV). While both be infected HIV, HIV viral proteins local environment interact activate these cells. Given play critical roles maintaining function, it will have an understanding of heterogeneity identify genes mechanisms modulate responses HIV. Heterogeneity may include a depletion or increase one more astrocyte microglial subtypes different regions brain spine as well gain loss specific function. Single-cell RNA sequencing (scRNA-seq) has emerged powerful tool used characterise given population. The use this method facilitates identification cellular transcriptomes develop activation various disease processes. In review, we examine recent studies scRNA-seq explore neurodegenerative diseases including Alzheimer’s amyotrophic lateral sclerosis infection. A careful review expand our current at states.

Язык: Английский

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Tackling the glial scar in spinal cord regeneration: new discoveries and future directions

Frontiers in Cellular Neuroscience, Год журнала: 2023, Номер 17

Опубликована: Май 24, 2023

Axonal regeneration and functional recovery are poor after spinal cord injury (SCI), typified by the formation of an scar. While this scar was traditionally believed to be primarily responsible for axonal failure, current knowledge takes a more holistic approach that considers intrinsic growth capacity axons. Targeting SCI has also not reproducibly yielded nearly same efficacy in animal models compared these neuron-directed approaches. These results suggest major reason behind central nervous system (CNS) failure is but stimulate axon adequately. findings raise questions about whether targeting neuroinflammation glial scarring still constitute viable translational avenues. We provide comprehensive review dual role how future research can produce therapeutic strategies hurdles posed processes without compromising neuroprotection.

Язык: Английский

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Current tools to interrogate microglial biology

Neuron, Год журнала: 2021, Номер 109(18), С. 2805 - 2819

Опубликована: Авг. 13, 2021

Язык: Английский

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Microglial functional alteration and increased diversity in the challenged brain: Insights into novel targets for intervention

Brain Behavior & Immunity - Health, Год журнала: 2021, Номер 16, С. 100301 - 100301

Опубликована: Июль 20, 2021

Microglia are the resident immune cells of central nervous system (CNS) parenchyma, which perform beneficial physiological roles across life. These actively maintain CNS health by clearing toxic debris and removing dysfunctional or degenerating cells. They also modify wiring neuronal circuits, acting on formation, modification, elimination synapses-the connections between neurons. furthermore recently emerged as highly diverse comprising several structural functional states, indicating a far more critical involvement in orchestrating brain development, plasticity, behaviour, cognition. Various environmental factors, together with individual genetic predispositions, confer an increased risk for neurodevelopmental neuropsychiatric disorders, well neurodegenerative diseases that include autism spectrum schizophrenia, major depressive disorder, Alzheimer's disease, sensitive to chronic psychological stress, inadequate diet, viral/bacterial infection, pollution, insufficient altered sleep, especially during developmental periods, but throughout challenges can compromise microglial functions, resulting notably defective circuit wiring, connectivity, onset behavioral deficits into adolescence, adulthood, aging. This short review provides historical technical perspective, focused my contribution field, how affect microglia, particularly their increase diversity, novel targets intervention.

Язык: Английский

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