The role of microglia in early neurodevelopment and the effects of maternal immune activation

Seminars in Immunopathology, Journal Year: 2024, Volume and Issue: 46(1-2)

Published: July 1, 2024

Activation of the maternal immune system during gestation has been associated with an increased risk for neurodevelopmental disorders in offspring, particularly schizophrenia and autism spectrum disorder. Microglia, tissue-resident macrophages central nervous system, are implicated as potential mediators this risk. Early development, microglia start populating embryonic addition to their traditional role responders under homeostatic conditions, also intricately involved various early processes. The timing activation may interfere functioning neurodevelopment, potentially leading long-term consequences postnatal life. In review we will discuss involvement brain development prenatal stages life, while examining effects on Additionally, recent single cell RNA-sequencing studies focusing hypothesize how life microglial priming, through epigenetic reprogramming, be related disorders.

Language: Английский

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Electromagnetic pulse exposure induces neuroinflammation and blood-brain barrier disruption by activating the NLRP3 inflammasome/NF-κB signaling pathway in mice

Ecotoxicology and Environmental Safety, Journal Year: 2025, Volume and Issue: 292, P. 117972 - 117972

Published: Feb. 27, 2025

Language: Английский

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Microglia pack a toolbox for life

Trends in Immunology, Journal Year: 2024, Volume and Issue: 45(5), P. 338 - 345

Published: April 13, 2024

Language: Английский

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Microglial heterogeneity in the ischemic stroke mouse brain of both sexes

Genome Medicine, Journal Year: 2024, Volume and Issue: 16(1)

Published: Aug. 2, 2024

Ischemic stroke elicits a complex and sustained immune response in the brain. Immunomodulatory treatments have long held promise for improving outcomes, yet none succeeded clinical setting. This lack of success is largely due to our incomplete understanding how cells respond stroke. The objective current study was dissect effect permanent on microglia, resident within brain parenchyma. A middle cerebral artery occlusion (pMCAO) model used induce ischemic young male female mice. Microglia were sorted from fluorescence reporter mice after pMCAO or sham surgery then subjected single-cell RNA sequencing analysis. Various methods, including flow cytometry, situ hybridization, immunohistochemistry, whole-brain imaging, bone marrow transplantation, also employed microglial Stroke outcomes evaluated by infarct size behavioral tests. First, we showed morphologic spatial changes microglia We performed analysis isolated both sexes. data indicate no major sexual dimorphism Notably, identified seven potential stroke-associated clusters, four clusters characterized disease-associated microglia-like signature, highly proliferative state, macrophage-like profile, an interferon (IFN) respectively. Importantly, provided evidence that cluster may represent long-sought stroke-induced subpopulation with increased CD45 expression. Lastly, given IFN-responsive subset constitutes most prominent population brain, fludarabine pharmacologically target STAT1 signaling found treatment improved long-term outcome. Our findings shed new light heterogeneity pathology underscore targeting specific populations effective therapies.

Language: Английский

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Mechanisms and environmental factors shaping the ecosystem of brain macrophages

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Jan. 24, 2025

Brain macrophages encompass two major populations: microglia in the parenchyma and border-associated (BAMs) extra-parenchymal compartments. These cells play crucial roles maintaining brain homeostasis immune surveillance. Microglia BAMs are phenotypically epigenetically distinct exhibit highly specialized functions tailored to their environmental niches. Intriguingly, recent studies have shown that both originate from same myeloid progenitor during yolk sac hematopoiesis, but developmental fates diverge within brain. Several works partially unveiled mechanisms orchestrating development of mice humans; however, many questions remain unanswered. Defining molecular underpinnings controlling transcriptional epigenetic programs is one upcoming challenges for field. In this review, we outline current knowledge on ontogeny, phenotypic diversity, factors shaping ecosystem macrophages. We discuss insights garnered human studies, highlighting similarities differences compared mice. Lastly, address research gaps potential future directions Understanding how communicate with local environment tissue instructs trajectories functional features essential fully comprehend physiology disease.

Language: Английский

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Microglial plasticity governed by state-specific enhancer landscapes

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

SUMMARY Single-cell transcriptomic studies have identified distinct microglial subpopulations with shared and divergent gene signatures across development, aging disease. Whether these subsets represent ontogenically separate lineages of cells, or they are manifestations plastic changes states downstream some converging signals is unknown. Furthermore, despite the well-established role enhancer landscapes underlying identity microglia, to what extent histone modifications DNA methylation regulate state switches at enhancers not been defined. Here, using genetic fate mapping, we demonstrate common embryonic origin proliferative-region-associated microglia (PAM) enriched in developing white matter, track their dynamic transitions into disease-associated (DAM) matter-associated (WAM) disease contexts, respectively. This study links spatiotemporally discrete through epigenomic plasticity, while revealing state-specific modification profiles that govern health

Language: Английский

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H4K12 Lactylation Activated‐Spp1 in Reprogrammed Microglia Improves Functional Recovery After Spinal Cord Injury

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(2)

Published: Feb. 1, 2025

ABSTRACT Background Spinal cord injury (SCI) is a severe condition leading to significant disability and high mortality. The role of the secreted phosphoprotein 1 (SPP1) signaling pathway in SCI, which quickly activated after injury, critical for intercellular communication but remains poorly understood. Aims This study aimed explore function regulatory mechanisms SPP1 SCI investigate its potential as therapeutic target improving functional recovery injury. Materials Methods Single‐cell RNA sequencing (scRNA‐seq) was employed identify ligands receptors pathway, particularly microglia/macrophages. Recombinant (rSPP1) used vitro vivo assess effects on neuronal maturation, mitochondrial energy axons, SCI. Pseudotime analysis conducted examine Spp1 microglial activation proliferation. DNA‐pulldown experiments were performed upstream proteins . Results primarily localized microglia with rSPP1 promoting maturation enhancing axons. Injection into injured spinal resulted improvement recovery. indicated that involved proliferation microglia. Histone H4 lysine 12 lactylation (H4K12la) found promote transcription reprogrammed postinjury. Discussion Our findings reveal novel mechanism involving activation, function, glycolytic reprogramming. new insight provides deeper understanding contribution response. Conclusion uncovers previously unreported offering

Language: Английский

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Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease

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

Published: April 1, 2025

Language: Английский

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Single-cell, single-nucleus and xenium-based spatial transcriptomics analyses reveal inflammatory activation and altered cell interactions in the hippocampus in mice with temporal lobe epilepsy

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Sept. 13, 2024

Abstract Background Temporal lobe epilepsy (TLE) is among the most common types of and often leads to cognitive, emotional, psychiatric issues due frequent seizures. A notable pathological change related TLE hippocampal sclerosis (HS), which characterized by neuronal loss, gliosis, an increased neuron fibre density. The mechanisms underlying TLE-HS development remain unclear, but reactive transcriptomic changes in glial cells neurons hippocampus post-epileptogenesis may provide insights. Methods To induce TLE, 200 nl kainic acid (KA) was stereotactically injected into CA1 region mice, followed a 7-day postinjection period. Single-cell RNA sequencing (ScRNA-seq), single-nucleus (SnRNA-seq), Xenium-based spatial transcriptomics analyses were employed evaluate mRNA expression neurons. Results From ScRNA-seq SnRNA-seq data, 31,390 48,221 nuclei identified. Analysis differentially expressed genes (DEGs) revealed significant alterations mice with affecting hundreds thousands mRNAs their signalling pathways. Enrichment analysis indicated activation stress inflammatory pathways hippocampus, while axonal neural support suppressed. Xenium demonstrated all 247 across mouse brain sections, revealing distributions 27 cell types. Integrated DEGs identified via three techniques that Spp1 , Trem2 Cd68 upregulated data; Penk Sorcs3 Plekha2 Tle4 Sipa1l3 downregulated data. Conclusion In this study, high-resolution single-cell atlas established, potential intrinsic driving TLE-associated altered interactions. These findings valuable insights for further exploration HS epileptogenesis.

Language: Английский

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Single-cell RNA sequencing in stroke and traumatic brain injury: Current achievements, challenges, and future perspectives on transcriptomic profiling

Journal of Cerebral Blood Flow & Metabolism, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

Single-cell RNA sequencing (scRNA-seq) is a high-throughput transcriptomic approach with the power to identify rare cells, discover new cellular subclusters, and describe novel genes. scRNA-seq can simultaneously reveal dynamic shifts in phenotypes heterogeneities subtypes. Since publication of first protocol on 2009, this evolving technology has continued improve, through use cell-specific barcodes, adoption droplet-based systems, development advanced computational methods. Despite induction stress response during tissue dissociation process, remains popular technology, commercially available methods have been applied brain. Recent advances spatial transcriptomics now allow researcher capture positional context transcriptional activity, strengthening our knowledge organization cell-cell interactions spatially intact tissues. A combination data proteomic, metabolomic, or chromatin accessibility promising direction for future research. Herein, we provide an overview workflow, analyses methods, pros cons technology. We also summarize latest achievements stroke acute traumatic brain injury, applications transcriptomics.

Language: Английский

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