Bi-directional neuro-immune dysfunction after chronic experimental brain injury

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: April 5, 2024

Abstract Background It is well established that traumatic brain injury (TBI) causes acute and chronic alterations in systemic immune function changes contribute to posttraumatic neuroinflammation neurodegeneration. However, how TBI affects bone marrow (BM) hematopoietic stem/progenitor cells chronically what extent such may negatively impact innate immunity neurological has not been examined. Methods To further understand the role of BM cell derivatives on outcome, we generated chimeric mice by transplanting from injured or sham (i.e., 90 days post-surgery) congenic donor into otherwise healthy, age-matched, irradiated CD45.2 C57BL/6 (WT) hosts. Immune were evaluated flow cytometry, multiplex ELISA, NanoString technology. Moderate-to-severe was induced controlled cortical measured using a battery behavioral tests. Results transcriptome lineage − c-Kit + Sca1 (LSK+) mice, including modified epigenetic senescence pathways. After 8 weeks reconstitution, peripheral myeloid TBI→WT showed significantly higher oxidative stress levels reduced phagocytic activity. At eight months after leukopenic, with continued phagocytosis responses, as persistent deficits. Gene expression analysis revealed BM-driven neuropathology respectively. Chimeric subjected at post-reconstitution longer reconstitution periods time post-injury) associated increased microgliosis leukocyte infiltration. Pre-treatment senolytic agent, ABT-263, improved performance aged baseline, although it did attenuate acutely brain. Conclusions activation progressive dysfunction pool, which drives long-term deficits hematopoiesis, immunity, function, altered sensitivity subsequent injury.

Language: Английский

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Insights into Calpain Activation and Rho-ROCK Signaling in Parkinson’s Disease and Aging

Biomedicines, Journal Year: 2024, Volume and Issue: 12(5), P. 1074 - 1074

Published: May 13, 2024

Parkinson’s disease (PD), a progressive neurodegenerative disease, has no cure, and current therapies are not effective at halting progression. The affects mid-brain dopaminergic neurons and, subsequently, the spinal cord, contributing to many debilitating symptoms associated with PD. GTP-binding protein, Rho, plays significant role in cellular pathology of downstream effector Rho-associated kinase (ROCK), multiple functions, including microglial activation induction inflammatory responses. Activated microglia have been implicated diseases, PD, that initiate responses, leading neuron death. Calpain expression activity is increased following glial activation, which triggers Rho-ROCK pathway induces T cell migration as well mediates toxic α-synuclein (α-syn) aggregation death, indicating pivotal for calpain degenerative processes Increased may represent new mechanism oxidative damage aging. This review will summarize stress α-syn aggregation, their influence on process PD aging, possible strategies research directions therapeutic intervention.

Language: Английский

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Acutely blocking excessive mitochondrial fission prevents chronic neurodegeneration after traumatic brain injury

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: 5(9), P. 101715 - 101715

Published: Sept. 1, 2024

Progression of acute traumatic brain injury (TBI) into chronic neurodegeneration is a major health problem with no protective treatments. Here, we report that acutely elevated mitochondrial fission after TBI in mice triggers persisting 17 months later, equivalent to many human decades. We show increased mouse related levels 1 protein (Fis1) and Fis1 also TBI. Pharmacologically preventing from binding its partner, dynamin-related (Drp1), for 2 weeks normalizes the balance fission/fusion prevents chronically impaired bioenergetics, oxidative damage, microglial activation lipid droplet formation, blood-brain barrier deterioration, neurodegeneration, cognitive impairment. Delaying treatment until 8 offers protection. Thus, time-sensitive inhibition may represent strategy protect patients neurodegeneration.

Language: Английский

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Cellular Senescence in Glial Cells: Implications for Multiple Sclerosis

Journal of Neurochemistry, Journal Year: 2025, Volume and Issue: 169(1)

Published: Jan. 1, 2025

ABSTRACT Aging is the most common risk factor for Multiple Sclerosis (MS) disease progression. Cellular senescence, irreversible state of cell cycle arrest, main driver aging and has been found to accumulate prematurely in neurodegenerative diseases, including Alzheimer's Parkinson's disease. senescence central nervous system MS patients recently gained attention, with several studies providing evidence that demyelination induces cellular hallmarks p16INK4A p21 expression, oxidative stress, senescence‐associated secreted factors. Here we discuss current animal models different glial populations system, highlighting major gaps field still remain. As premature may exacerbate inflammation, resulting inhibition myelin repair, it critical increase understanding vivo, functional effects on cells, impact removing senescent cells remyelination MS. This emerging holds promise opening new avenues treatment patients. image

Language: Английский

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Microglial Autophagic Dysregulation in Traumatic Brain Injury: Molecular Insights and Therapeutic Avenues

ACS Chemical Neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Traumatic brain injury (TBI) is a complex and multifaceted condition that can result in cognitive behavioral impairments. One aspect of TBI has received increasing attention recent years the role microglia, brain-resident immune cells, pathophysiology injury. Specifically, evidence suggests dysfunction microglial autophagy, process by which cells degrade recycle their own damaged components, may contribute to development progression TBI-related Here, we unravel pathways microglia autophagic dysregulation predisposes secondary damage neurological deficits following TBI. An overview perpetuation worsening inflammatory response, neuroinflammation, neuronal cell death follows. Further, have evaluated several signaling processes autophagy dysfunction-mediated inflammation, neurodegeneration, poor outcome Additionally, discussion on small molecule therapeutics employed modulate these mechanisms treat been presented. However, additional research required fully understand behind underlying uncover potential therapeutic targets for restoring failure

Language: Английский

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Diffuse Traumatic Brain Injury Induced Stimulator of Interferons (STING) Signaling in Microglia Drives Cortical Neuroinflammation, Neuronal Dysfunction, and Impaired Cognition

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 17, 2025

Neuropsychiatric complications including depression and cognitive impairment develop, persist, worsen in the years after traumatic brain injury (TBI), negatively affecting life lifespan. Inflammatory responses mediated by microglia are associated with transition from acute to chronic neuroinflammation TBI. Moreover, type I interferon (IFN-I) signaling is a key mediator of inflammation during this transition. Thus, purpose study was determine degree which microglia-specific knockout stimulator interferons (STING) influenced TBI-induced neuroinflammation, neuronal dysfunction, impairment. Here, microglial inducible STING (CX₃CR1Cre/ERT2 x STING^fl/fl) mice were created validated (mSTING^-/-). Diffuse (midline fluid percussion) male female increased expression microglia, promoted morphological restructuring, induced robust cortical pathology 7 days post (dpi). These TBI-associated attenuated mSTING^-/- mice. Increased astrogliosis rod-shaped TBI independent mSTING^-/-. dpi, 237 differentially expressed genes (DEG) cortex functionally wildtype (STING^+/+) associated STING, NF- κB, Interferon Alpha 85% Components reduced NeuN expression, lipofuscin, neurofilament light chain plasma dependent on mSTING. tasks (novel object recognition/location, NOR/NOL) at dpi Notably, deficits NOR/NOL unaffected global interferon-α/β receptor 1 (IFNAR1) In final study, RNA profile neurons STING^+/+ assessed single nucleus RNA-sequencing. There TBI-dependent suppression homeostasis reductions CREB signaling, synaptogenesis, oxytocin increases cilium assembly PTEN signaling. Overall, prevented 50% DEGs neurons. Collectively, ablation attenuates IFN-dependent responses, inflammation, pathology,

Language: Английский

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Illuminating Immunity: A Systematic Review of Immune Cell Autofluorescence

Journal of Biophotonics, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Immunophenotyping provides valuable prognostic and diagnostic information, but is technically complex expensive. The assessment of autofluorescence label-free information on cell identity. However, research its application to immunophenotyping has been heterogenous. This systematic review was carried out identify synthesise all available evidence the use for immunophenotyping. Eighty three full texts were included. There a focus neutrophils (20 papers) macrophages (22 with alveolar (13 forming subcategory. Seven studies investigated monocytes, focused microglia, two dendritic cells, five mast nine granulocytes, thirteen eosinophils, one erythrophagocytic natural killer cells. Eleven uncategorised immune populations. Translation findings into clinical requires reproducible methods, along clear reporting excitation emission parameters, greater primary samples.

Language: Английский

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Constructed transferrin receptor-targeted liposome for the delivery of fluvoxamine to improve prognosis in a traumatic brain injury mouse model

Drug Delivery, Journal Year: 2025, Volume and Issue: 32(1)

Published: April 15, 2025

The dysregulation of blood-brain barrier (BBB) activates pathological mechanisms such as neuroinflammation after traumatic brain injury (TBI), and glymphatic system dysfunction accelerates toxic waste accumulation TBI. It is essential to find an effective way inhibit inflammation repair BBB TBI; however, lasting drug therapy remains challenging because severely prevents drugs from being delivered central nervous system. Transferrin receptors (TfRs) are mainly expressed on capillary endothelial cells. Here, we report a TfR-targeted nanomedicine for TBI treatment by penetrating delivering fluvoxamine (Flv). polypeptide liposome loaded with Flv (TPL-Flv) implements cell targeting ability human umbilical vein cells (HUVECs) in vitro detected flow cytometry, safety was proved through viability analysis blood routine biochemistry analysis. Afterwards, established controlled cortical impact model explore TPL-Flv administration effects mice. We confirmed that could stimulate CXCR4/SDF-1 signaling pathway, activate Treg cells, also alleviated disruption restored aquaporin-4 (AQP4) polarization, well reversed dysfunction. Furthermore, accomplished remarkable improvement motor cognitive functions. These findings demonstrate can effectively cross achieve delivery cerebral tissue, validating its potential improve therapeutic outcomes

Language: Английский

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Pathophysiologic Mechanisms of Severe Spinal Cord Injury and Neuroplasticity Following Decompressive Laminectomy and Expansive Duraplasty: A Systematic Review

Neurology International, Journal Year: 2025, Volume and Issue: 17(4), P. 57 - 57

Published: April 16, 2025

Background: Severe spinal cord injury (SCI) represents a debilitating condition with long-term physical and socioeconomic impacts. Understanding the pathophysiology of SCI therapeutic interventions such as decompressive laminectomy expansive duraplasty is crucial for optimizing patient outcomes. Objective: This systematic review explores evaluates evidence linking to improved neuroplasticity recovery. Methods: A comprehensive search was conducted in PubMed, Web Science, Cochrane Library studies on surgery SCI. Inclusion criteria were original articles investigating pathophysiology, mechanisms, or surgical Data pathophysiological changes, molecular markers, functional outcomes extracted. Results: From 1240 initial articles, 43 included, encompassing both animal models human clinical data. Findings highlighted role inflammatory cascades, blood–spinal barrier disruption, neurotrophic factor modulation Decompressive associated intrathecal pressure (ITP) management BDNF GAP-43. Conclusions: underscores potential While suggests benefits promoting neuroplasticity, further research needed elucidate mechanisms refine interventions.

Language: Английский

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Diffuse traumatic brain injury induced stimulator of interferons (STING) signaling in microglia drives cortical neuroinflammation, neuronal dysfunction, and impaired cognition

Journal of Neuroinflammation, Journal Year: 2025, Volume and Issue: 22(1)

Published: April 30, 2025

Language: Английский

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