Complement C1q drives microglia-dependent synaptic loss and cognitive impairments in a mouse model of lipopolysaccharide-induced neuroinflammation

Neuropharmacology, Год журнала: 2023, Номер 237, С. 109646 - 109646

Опубликована: Июнь 24, 2023

Язык: Английский

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Oxytocin alleviates cognitive and memory impairments by decreasing hippocampal microglial activation and synaptic defects via OXTR/ERK/STAT3 pathway in a mouse model of sepsis-associated encephalopathy

Brain Behavior and Immunity, Год журнала: 2023, Номер 114, С. 195 - 213

Опубликована: Авг. 28, 2023

Язык: Английский

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STING inhibition suppresses microglia-mediated synapses engulfment and alleviates motor functional deficits after stroke

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Апрель 8, 2024

Abstract Ischemic stroke is the leading cause of adult disability. Ischemia leads to progressive neuronal death and synapse loss. The engulfment stressed synapses by microglia further contributes disruption surviving network related brain function. Unfortunately, there currently no effective target for suppressing microglia-mediated engulfment. Stimulator interferon genes (STING) an important participant in innate immune response. In brain, are primary cell type that mediate response after insult. intimate relationship between STING neuroinflammation has been gradually established. However, whether affects other functions remains elusive. this study, we found regulated microglial phagocytosis photothrombotic stroke. treatment inhibitor H151 significantly improved behavioral performance injured mice grid-walking test, cylinder adhesive removal test Moreover, puncta number engulfed SYP or PSD95 was reduced consecutive administration. Further analysis showed mRNA levels several complement components phagocytotic receptors were decreased inhibition. Transcriptional factor STAT1 known regulating most molecules. After inhibition, nucleus translocation phosphorylated also suppressed microglia. Our data uncovered novel regulatory effects stroke, emphasized as a potential drug-able post-stroke functional recovery.

Язык: Английский

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Targeted rescue of synaptic plasticity improves cognitive decline in sepsis-associated encephalopathy

Molecular Therapy, Год журнала: 2024, Номер 32(7), С. 2113 - 2129

Опубликована: Май 23, 2024

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE murine peritoneal contamination (PCI) model. found long-lasting synaptic pathology the hippocampus including defective plasticity, reduction mature neuronal dendritic spines, severely affected excitatory neurotransmission. Genes related to signaling, gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) members transcription-regulatory EGR family, were downregulated. At level, ARC expression mitogen-activated kinase signaling brain affected. For targeted rescue we used adeno-associated virus-mediated overexpression vivo. This recovered plasticity improved memory dysfunction. Using enriched environment paradigm as non-invasive intervention, improvement potentiation, memory, anxiety. The beneficial effects an accompanied by increase brain-derived neurotrophic factor (BDNF) hippocampus, suggesting that activation BDNF-TrkB pathway leads restoration PCI-induced ARC. Collectively, our findings identify pathomechanisms underlying provide conceptual approach target SAE-induced dysfunction with potential therapeutic applications patients SAE.

Язык: Английский

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Clec7a Worsens Long‐Term Outcomes after Ischemic Stroke by Aggravating Microglia‐Mediated Synapse Elimination

Advanced Science, Год журнала: 2024, Номер unknown

Опубликована: Авг. 1, 2024

Abstract Ischemic stroke (IS) is a leading cause of morbidity and mortality globally triggers series reactions to primary secondary brain injuries permanent neurological deficits. Microglia in the central nervous system play dual roles neuroprotection responding ischemic damage. Here, an IS model employed determine involvement microglia phagocytosis at excitatory synapses. Additionally, effects pharmacological depletion are investigated on improving neurobehavioral outcomes mitigating injury. RNA sequencing reveals increase phagocytosis‐associated pathway activity gene expression, C‐type lectin domain family 7 member A (Clec7a) identified as key regulator this process. Manipulating microglial Clec7a expression can potentially regulate synapses, thereby preventing synaptic loss after IS. It further demonstrat that interacts with neuronal myeloid differentiation protein 2 (MD2), molecule mediating poststroke injury, propose novel hypothesis MD2 ligand for Clec7a. These findings suggest plays critical role mouse IS, suggesting may be therapeutic target

Язык: Английский

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The impact of neuroinflammation on neuronal integrity

Immunological Reviews, Год журнала: 2024, Номер 327(1), С. 8 - 32

Опубликована: Окт. 1, 2024

Neuroinflammation, characterized by a complex interplay among innate and adaptive immune responses within the central nervous system (CNS), is crucial in responding to infections, injuries, disease pathologies. However, dysregulation of neuroinflammatory response could significantly affect neurons terms function structure, leading profound health implications. Although tremendous progress has been made understanding relationship between processes alterations neuronal integrity, specific implications concerning both structure have not extensively covered, with exception perspectives on glial activation neurodegeneration. Thus, this review aims provide comprehensive overview multifaceted interactions key inflammatory players, exploring mechanisms through which inflammation influences functionality structural integrity CNS. Further, it will discuss how these lead impairment functions architecture highlight consequences caused dysregulated functions, such as cognitive dysfunction mood disorders. By integrating insights from recent research findings, enhance our landscape set stage for future interventions that transform current approaches preserve CNS-related conditions.

Язык: Английский

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Growth differentiation factor 15 aggravates sepsis-induced cognitive and memory impairments by promoting microglial inflammatory responses and phagocytosis

Journal of Neuroinflammation, Год журнала: 2025, Номер 22(1)

Опубликована: Фев. 21, 2025

Sepsis-associated encephalopathy (SAE) is a severe neurological condition caused by sepsis, and presents with symptoms ranging from delirium coma to long-term cognitive dysfunction. SAE acknowledged as widespread brain impairment characterized the activation of microglia. However, specific pathological mechanisms that drive this are still not clearly understood. Growth differentiation factor 15 (GDF15) levels have been noted be considerably increased in patients where they linked disease severity can independently predict short- mortality risk. Serum GDF15 also negatively associated gray matter volume older individuals. impact on sepsis-induced memory impairments, well behind these effects, poorly To examine role SAE, sepsis model was created adult C57BL/6J mice using intraperitoneal administration lipopolysaccharide (LPS). plasma cerebrospinal fluid were measured ELISA. The anti-GDF15 monoclonal antibody ponsegromab injected intracerebroventricularly before modeling, functions septic assessed fear-conditioning novel object recognition tests. Microglial phagocytosis evaluated immunofluorescence Golgi staining. Additionally, an vitro investigation LPS-stimulated microglia conducted evaluate impacts inflammatory cytokine productions microglial phagocytic activity. Mechanisms explored RNA sequencing, qPCR, western blotting, flow cytometry, assays. In mice, notably elevated after injection LPS. Lateral ventricular alleviated both together hippocampus, thereby protecting against synaptic loss. brains mice. Targeting found improve reducing response phagocytosis. These results indicate could serve important therapeutic target for treating SAE.

Язык: Английский

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Limitations of PLX3397 as a microglial investigational tool: peripheral and off-target effects dictate the response to inflammation

Frontiers in Immunology, Год журнала: 2023, Номер 14

Опубликована: Ноя. 22, 2023

Microglia, the resident macrophages of central nervous system (CNS), play a critical role in CNS homeostasis and neuroinflammation. Pexidartinib (PLX3397), colony-stimulating factor 1 (CSF1) receptor inhibitor, is widely used to deplete microglia, offering flexible options for both long-term depletion highly versatile depletion-repopulation cycles. However, potential impact PLX3397 on peripheral (immune) cells remains controversial. Until now, microglia-specificity this type compounds has not been thoroughly evaluated, particularly context peripherally derived Our study addresses gap by examining effects immune brain, liver, circulation bone marrow, systemic inflammation models. Intriguingly, we demonstrate that treatment only influences levels tissue-resident macrophages, but also affects circulating marrow beyond mononuclear phagocyte (MPS). These alterations disrupt response inflammation, consequently impacting phenotype irrespective microglial depletion. Furthermore, observed lower dose PLX3397, which does demonstrates similar (non-)MPS effects, periphery fails fully replicate seen higher doses, questioning doses as ‘peripheral control’ strategy. Overall, our data highlight need caution when interpreting studies employing compound, it may be suitable specific investigation function presence inflammation.

Язык: Английский

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Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity

Cell & Bioscience, Год журнала: 2024, Номер 14(1)

Опубликована: Апрель 1, 2024

Abstract Background Repeated neonatal sevoflurane exposures led to neurocognitive disorders in young mice. We aimed assess the role of microglia and complement C1q sevoflurane-induced neurotoxicity explore underlying mechanisms. Methods Neonatal mice were treated with on postnatal days 6, 8, 10, Morris water maze was performed cognitive functions. For mechanistic explorations, minocycline, C1q-antibody ANX005, sialidase-inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA) before exposures. Western blotting, RT-qPCR, Golgi staining, 3D reconstruction engulfment analysis, immunofluorescence, microglial morphology analysis performed. In vitro experiments conducted cell line BV2 cells. Results resulted deficiencies learning cognition mice, accompanied by activation synapse loss. Sevoflurane enhanced microglia-mediated elimination through binding synapses. Inhibition phagocytosis minocycline significantly reduced loss further revealed involvement neuronal sialic acids this process. The activity sialidase acids, which facilitated ANX005 or inhibition NADNA rescued improved function. cells, reversed ANX005. Conclusions Our findings demonstrated that C1q-mediated synaptic enhancing desialylation contributed developmental neurotoxicity. may be a potential therapeutic strategy for

Язык: Английский

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Immunotherapy in the context of sepsis-induced immunological dysregulation

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Май 21, 2024

Sepsis is a clinical syndrome caused by uncontrollable immune dysregulation triggered pathogen infection, characterized high incidence, mortality rates, and disease burden. Current treatments primarily focus on symptomatic relief, lacking specific therapeutic interventions. The core mechanism of sepsis believed to be an imbalance in the host's response, early excessive inflammation followed late suppression, invasion. This suggests that we can develop immunotherapeutic treatment strategies targeting modulating components immunological functions innate adaptive systems. Therefore, this paper reviews mechanisms and, based foundation, discusses current state immunotherapy applications animal models trials.

Язык: Английский

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