Repeated LPS induces training and tolerance of microglial responses across brain regions

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

Published: Sept. 20, 2024

Neuroinflammation is involved in the pathogenesis of almost every central nervous system disorder. As brain's innate immune cells, microglia fine tune their activity to a dynamic brain environment. Previous studies have shown that repeated bouts peripheral inflammation can trigger long-term changes microglial gene expression and function, form memory.

Language: Английский

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To re-examine the intersection of microglial activation and neuroinflammation in neurodegenerative diseases from the perspective of pyroptosis

Frontiers in Aging Neuroscience, Journal Year: 2023, Volume and Issue: 15

Published: Nov. 9, 2023

Neurodegenerative diseases (NDs), such as Alzheimer’s disease, Parkinson’s Huntington’s and motor neuron are characterized by neuronal damage dysfunction. NDs considered to be a multifactorial disease with diverse etiologies (immune, inflammatory, aging, genetic, etc.) complex pathophysiological processes. Previous studies have found that neuroinflammation typical microglial activation important mechanisms of NDs, leading neurological dysfunction progression. Pyroptosis is new mode involved in this process. As form programmed cell death, pyroptosis the expansion cells until membrane bursts, resulting release contents activates strong inflammatory response promotes accelerating abnormal activation. In case, abnormally activated microglia various pro-inflammatory factors, occurrence exacerbating both pyroptosis, thus forming vicious cycle. The recognition association between activation, well neuroinflammation, significant importance understanding pathogenesis providing targets strategies for their prevention treatment.

Language: Английский

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Spreading depolarization triggers pro- and anti-inflammatory signalling: a potential link to headache

Brain, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract Cortical spreading depolarization (CSD), the neurophysiological event believed to underlie aura, may trigger migraine headaches through inflammatory signaling that originates in neurons and spreads meninges via astrocytes. Increasing evidence from studies on rodents patients supports this hypothesis. The transition pro-inflammatory anti-inflammatory mechanisms is crucial for resolving inflammation. However, resolution of inflammation context CSD remains poorly understood. This study aims elucidate progression post-CSD its neurons, astrocytes, microglia mouse brains. was triggered optogenetically or by pinprick. HMGB1 release, caspase-1 activation, cell-specific activation NF-κB pairs, along with ensuing transcriptomic changes, were evaluated using immunofluorescence, Western blotting, co-immunoprecipitation, FRET analysis, transcriptomics. Our findings indicate after initial burst, release ceased, which peaked 1-hour post-CSD, diminished within 3-5 hours. suggests stimuli driving decreased hours CSD. Pro-inflammatory p65:p50 cRel:p65 detected astrocyte nuclei shortly 24 former had disappeared while latter persisted, indicating a shift activity Pathway analysis data confirmed NF-κB-related transcription astrocytes no such observed neurons. Detailed Bayesian cell proportion reconstruction revealed exhibited transcriptional changes trending towards an profile, upregulation several chemokines cytokines (e.g., TNF). play role supporting responses these mediators. genes involved chemotaxis Ccl3) spine pruning C1q) implies contribute synaptic repair, could potentially modulate meningeal nociceptor extensive endfeet syncytium abutting subarachnoid perivascular spaces although direct incomplete. nuanced understanding response CNS types highlights intricate cellular interactions Following single CSD, distinct occur microglia, responses, contributing headache initiation resolution.

Language: Английский

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Mechanisms of astrocytic and microglial purinergic signaling in homeostatic regulation and implications for neurological disease

Exploration of neuroscience, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Purinergic signaling, mediated by ATP and adenosine receptors, plays a crucial role in cellular communication homeostasis within the central nervous system (CNS), particularly regulating synaptic activity, glial cell functions, neuroplasticity. Glial cells, including astrocytes microglia, contribute to both short-term processes, such as neurotransmission neuroinflammation, long-term remodeling, tissue repair, behavioral adaptation. Dysregulation of purinergic signaling these cells has been implicated pathogenesis various neurodegenerative neuropsychiatric disorders. This article explores evolving concept synapse, highlighting active modulation emphasizing significance function responses conditions injury neurotoxicity. Specifically, it examines roles receptors—such P2X4, P2X7, P2Y1, P2Y12—in mediating key astrocytic microglial phagocytosis, plasticity, neuronal damage. Furthermore, discusses involvement receptors neurological disorders epilepsy, Alzheimer’s disease, Parkinson’s multiple sclerosis, ischemic stroke, Rett syndrome, autism spectrum disorder, well potential therapeutic strategies targeting mitigate inflammation, promote improve clinical outcomes.

Language: Английский

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Evolution of Alzheimer’s Disease Therapeutics: From Conventional Drugs to Medicinal Plants, Immunotherapy, Microbiotherapy and Nanotherapy

Pharmaceutics, Journal Year: 2025, Volume and Issue: 17(1), P. 128 - 128

Published: Jan. 17, 2025

Alzheimer's disease (AD) represents an escalating global health crisis, constituting the leading cause of dementia among elderly and profoundly impairing their quality life. Current FDA-approved drugs, such as rivastigmine, donepezil, galantamine, memantine, offer only modest symptomatic relief are frequently associated with significant adverse effects. Faced this challenge in line advances understanding pathophysiology neurodegenerative condition, various innovative therapeutic strategies have been explored. Here, we review novel approaches inspired by advanced knowledge underlying pathophysiological mechanisms disease. Among alternatives, immunotherapy stands out, employing monoclonal antibodies to specifically target eliminate toxic proteins implicated AD. Additionally, use medicinal plants is examined, synergistic effects components may confer neuroprotective properties. The modulation gut microbiota also addressed a peripheral strategy that could influence neuroinflammatory degenerative processes brain. Furthermore, potential emerging approaches, microRNAs regulate key cellular nanotherapy, which enables precise drug delivery central nervous system, analyzed. Despite promising these strategies, incidence continues rise. Therefore, it proposed achieving effective treatment future require integration combined maximizing different interventions.

Language: Английский

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Pentadecyl®, an odd-chain-rich triglyceride mixture derived from Aurantiochytrium oil, attenuates lipopolysaccharide-induced inflammatory cytokine production in BV-2 microglial cells

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 158, P. 114810 - 114810

Published: May 10, 2025

Language: Английский

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Navigating the Blood–Brain Barrier: Challenges and Therapeutic Strategies in Breast Cancer Brain Metastases

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(15), P. 12034 - 12034

Published: July 27, 2023

Breast cancer (BC) is the most common in women, with metastatic BC being responsible for highest number of deaths. A frequent site metastasis brain. Brain derived from involves cooperation multiple genetic, epigenetic, angiogenic, and tumor–stroma interactions. Most these interactions provide a unique opportunity development new therapeutic targets. Potentially targetable signaling pathways are Notch, Wnt, epidermal growth factor receptors pathways, all which linked to driving brain (BCBM). However, major challenge treating remains blood–brain barrier (BBB). This restricts access unwanted molecules, cells, targeted therapies parenchyma. Moreover, current treat metastases, such as stereotactic radiosurgery whole-brain radiotherapy, have limited efficacy. Promising drugs like phosphatase kinase modulators, well BBB disruptors immunotherapeutic strategies, shown potential ease disease preclinical studies, but remain by resistance mechanisms. review summarizes some understanding mechanisms involved highlights challenges opportunities strategic designs potentially successful future therapies.

Language: Английский

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Repeated LPS induces training and tolerance of microglial responses across brain regions

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 12, 2024

Abstract Background Neuroinflammation is involved in the pathogenesis of almost every central nervous system disorder. As brain’s innate immune cells, microglia fine tune their activity to a dynamic brain environment. Previous studies have shown that repeated bouts peripheral inflammation can trigger long-term changes microglial gene expression and function, form memory. Methods Results In this study, we used multiple low-dose lipopolysaccharide (LPS) injections adult mice study acute cytokine, transcriptomic, morphological contribute formation memory frontal cortex, hippocampus, striatum, as well effects these on behavior. Training tolerance was shared across regions, identified 3 unique clusters DEGs (2xLPS-sensitive, 4xLPS-sensitive, LPS-decreased) with different biological functions. 2xLPS-sensitive DEG promoters were enriched for binding sites IRF NFkB family transcription factors, two key regulators We quantified shifts populations found while proportion ramified rod-like mostly remained consistent within regions sexes LPS treatment, there shift from ameboid towards hypertrophic states emergence resolution trains LPS. Conclusions Together, findings support regulation during memories future work exploit model disease contexts.

Language: Английский

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Protective effects of fatty acid amide hydrolase inhibition in UVB-activated microglia

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, Journal Year: 2024, Volume and Issue: 1869(7), P. 159524 - 159524

Published: June 12, 2024

Neuroinflammation is a hallmark of several neurodegenerative disorders that has been extensively studied in recent years. Microglia, the primary immune cells central nervous system (CNS), are key players this physiological process, demonstrating remarkable adaptability responding to various stimuli eye and brain. Within complex network neuroinflammatory signals, fatty acid N-ethanolamines, particular N-arachidonylethanolamine (anandamide, AEA), emerged as crucial regulators microglial activity under both pathological states. In study, we interrogated for first time impact signaling these bioactive lipids on cell responses sub-lethal acute UVB radiation, physical stressor responsible microglia reactivity either retina or To end, developed an vitro model using mouse BV-2 cells. Upon 24 h exposure, showed elevated oxidative stress markers and, cyclooxygenase (COX-2) expression, enhanced phagocytic chemotactic activities, along with altered profiling. Notably, exposure led selective increase expression amide hydrolase (FAAH), main enzyme degradation ethanolamides. Pharmacological FAAH inhibition via URB597 counteracted effects decreasing tumor necrosis factor α (TNF-α) nitric oxide (NO) release reverting reactive species (ROS), interleukin-1β (IL-1β), interleukin-10 (IL-10) levels control levels. Our findings support potential mitigating UVB-induced cellular damage, paving way further exploration light-induced responses.

Language: Английский

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Hypoxic stress dysregulates functions of glioma-associated myeloid cells through epigenomic and transcriptional programs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 16, 2024

ABSTRACT Hypoxia rapidly alters gene expression to allow cellular adaptation challenging conditions and support tumour growth. also affects the chromatin structure by modifications of histones DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain for which there no effective treatment. The microenvironment GBM highly heterogeneous, with infiltration glioma-associated microglia macrophages (GAMs) presence necrotic, hypoxic regions. mechanisms through hypoxia regulates functions infiltrating immune cells remain poorly understood. Here, we show that modulates myeloid markers in distinct ways: upregulates monocytic marker Lgals3 downregulates microglial P2ry12 Tmem119 GAMs vitro vivo , as shown using human mouse single-cell transcriptomics datasets. genome-wide hypoxia-dependent transcriptomic changes were determined microglia-glioma co-cultures. Numerous GAM subtype dysregulated response stress due associated accessibility, ATACseq. While alone drives a decrease overall accessibility at promoters, exposure glioma under leads both increases decreases promoter regions cells. enriched motifs transcription factors regarded master regulators cell identity function, including SPI1 or IRF8 . Overall, our data highlights importance strong intratumoral regulator functions, adds complexity characterisation particular subpopulations.

Language: Английский

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