Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD

Cancer Cell, Год журнала: 2024, Номер 42(8), С. 1450 - 1466.e11

Опубликована: Авг. 1, 2024

Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune strong anti-tumor activity and may offer a promising treatment strategy for GBM. We compared the anti-GBM of NK engineered to express interleukin (IL)-15 or IL-21. Using multiple in vivo models, IL-21 were superior IL-15 both terms safety long-term activity, locoregionally administered proving toxic ineffective at tumor control. displayed unique chromatin accessibility signature, CCAAT/enhancer-binding proteins (C/EBP), especially CEBPD, serving as key transcription factors regulating their enhanced function. Deletion CEBPD resulted loss cell potency while its overexpression increased cytotoxicity metabolic fitness. These results suggest that IL-21, through C/EBP factors, drives epigenetic reprogramming cells, enhancing efficacy against

Язык: Английский

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Quantifying microglial morphology: an insight into function

Clinical & Experimental Immunology, Год журнала: 2024, Номер 216(3), С. 221 - 229

Опубликована: Март 6, 2024

Microglia are specialized immune cells unique to the central nervous system (CNS). have a highly plastic morphology that changes rapidly in response injury or infection. Qualitative and quantitative measurements of ever-changing microglial considered cornerstone many microglia-centric research studies. The distinctive morphological variations seen microglia useful marker inflammation severity tissue damage. Although wide array damage-associated morphologies has been documented, exact functions these distinct not fully understood. In this review, we discuss how is synonymous with function, however, outcomes can be used make inferences about function. For comprehensive examination reactive status cell, both histological genetic approaches should combined. However, importance quality immunohistochemistry-based analyses overlooked as they succinctly answer questions.

Язык: Английский

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Neuroinflammation is associated with Alzheimer’s disease co-pathology in dementia with Lewy bodies

Acta Neuropathologica Communications, Год журнала: 2024, Номер 12(1)

Опубликована: Май 7, 2024

Neuroinflammation and Alzheimer's disease (AD) co-pathology may contribute to progression severity in dementia with Lewy bodies (DLB). This study aims clarify whether a different pattern of neuroinflammation, such as alteration microglial astroglial morphology distribution, is present DLB cases without AD co-pathology. The load (% area immunopositivity) total (Iba1) reactive microglia (CD68 HLA-DR), astrocytes (GFAP) proteinopathies alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) p-tau (AT8) were assessed cohort mixed + (n = 35), pure 15), 16) control 11) donors limbic neocortical brain regions using immunostaining, quantitative image analysis confocal microscopy. Regional group differences estimated linear model analysis. Morphologically, amoeboid common AD, while homeostatic small soma thin processes observed cases. A higher density swollen was cases, but not or Mixed had CD68-loads the amygdala parahippocampal gyrus than did differ astrocytic loads. Pure showed Iba1-loads CA1 CA2, CA2 subiculum, CA1-4 subiculum In associated strongly (Iba1, CD68 minimally (CD68). addition, highest activity found CA4. Confocal microscopy demonstrated co-localization large neuritic classic-cored plaques conclusion, activation largely co-pathology, response not. high regions, prevalent pathology. Our provides novel insights into molecular neuropathology DLB, highlighting importance AD.

Язык: Английский

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Label-Free Imaging of Inflammation at the Level of Single Cells in the Living Human Eye

Ophthalmology Science, Год журнала: 2024, Номер 4(5), С. 100475 - 100475

Опубликована: Янв. 21, 2024

PurposePutative microglia were recently detected using adaptive optics ophthalmoscopy in healthy eyes. Here we evaluate the use of non-confocal scanning light (AOSLO) for quantifying morphology and motility presumed other immune cells eyes with retinal inflammation from uveitis eyes.DesignObservational Exploratory Study.Participants12 participants imaged, including 8 4 posterior patients recruited clinic one authors (MHE).MethodsThe Pittsburgh AOSLO imaging system was used a custom-designed 7-fiber optical fiber bundle simultaneous confocal multi-offset detection. The inner retina imaged at several locations multiple timepoints to generate timelapse images.Main Outcome MeasuresMicroglia macrophages manually segmented images, their morphological characteristics quantified (including soma size, diameter, circularity). Cell motion across time periods up 30 minutes speeds calculated by measuring displacement over time.ResultsA spectrum cell morphologies circular amoeboid elongated visible processes, resembling activated ramified microglia, respectively. Average diameter 16.1 ± 0.9 μm. movement slow (0.02 μm/sec on average), but macrophage-like moved rapidly some (up 3 μm/sec). In an eye infectious uveitis, many detected; during treatment quantity decreased as vision improved.ConclusionsIn vivo offers promise potentially powerful tool detecting monitoring response cellular level living eye.

Язык: Английский

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Soma and neurite density abnormalities of paramagnetic rim lesions and core-sign lesions in multiple sclerosis

Journal of Neurology, Год журнала: 2025, Номер 272(2)

Опубликована: Янв. 15, 2025

Язык: Английский

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The Hallmarks of Ageing in Microglia

Cellular and Molecular Neurobiology, Год журнала: 2025, Номер 45(1)

Опубликована: Май 19, 2025

Abstract As ageing is linked to the development of neurodegenerative diseases (NDs), such as Alzheimer’s Disease and Parkinson’s Disease, it important disentangle independent effect age-related changes from those due disease processes. To do so, central nervous system (CNS) cells a function advanced age need better characterisation. Microglia are particular interest their proposed links with progression NDs through control CNS immune response. Therefore, understanding extent which microglial dysfunction related phyisological ageing, rather than process, critical. microglia age, they believed take on pro-inflammatory phenotype distinct dystrophic morphology. Nevertheless, while established hallmarks have been investigated across range other cell types, macrophages, detailed consideration functional that occur in aged remains elusive. Here, we describe dynamic phenotypes evaluate current state focusing recently updated twelve ageing. Understanding how these present represents step towards characterisation essential more representative models NDs. Graphical Microglial different stages life. diverse functions throughout life; however, has inconsistent

Язык: Английский

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Development of a High-Throughput Pipeline to Characterize Microglia Morphological States at a Single-Cell Resolution

eNeuro, Год журнала: 2024, Номер 11(7), С. ENEURO.0014 - 24.2024

Опубликована: Июль 1, 2024

As rapid responders to their environments, microglia engage in functions that are mirrored by cellular morphology. Microglia classically thought exhibit a ramified morphology under homeostatic conditions which switches an ameboid form during inflammatory conditions. However, display wide spectrum of morphologies outside this dichotomy, including rod-like, ramified, ameboid, and hypertrophic states, have been observed across brain regions, neurodevelopmental timepoints, various pathological contexts. We applied dimensionality reduction clustering consider contributions multiple measures together define microglial morphological states mouse dataset we used demonstrate the utility our toolset. Using ImageJ, first developed semiautomated approach characterize 27 features from hundreds thousands individual cells region-specific manner. Within pool features, defined distinct sets highly correlated describe different aspects morphology, branch length, branching complexity, territory span, circularity. When considered together, these drove clusters. Our tools captured similarly robustly when independent datasets using immunofluorescent markers for microglia. compiled analysis pipeline into accessible, easy-to-use, fully open-source ImageJ macro R package neuroscience community can expand upon directly apply own analyses. Outcomes work will supply field with new systematically evaluate heterogeneity experimental models research questions.

Язык: Английский

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Role of inflammation in a rat model of radiation retinopathy

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

Опубликована: Июнь 24, 2024

Abstract Radiation retinopathy (RR) is a major side effect of ocular tumor treatment by plaque brachytherapy or proton beam therapy. RR manifests as delayed and progressive microvasculopathy, ischemia macular edema, ultimately leading to vision loss, neovascular glaucoma, and, in extreme cases, secondary enucleation. Intravitreal anti-VEGF agents, steroids laser photocoagulation have limited effects on RR. The role retinal inflammation its contribution the microvascular damage occurring remain incompletely understood. To explore cellular vascular events after irradiation, we analyzed their time course at 1 week, month 6 months rat eyes received 45 Gy X-beam photons. Müller glial cells, astrocytes microglia were rapidly activated, these markers persisted for irradiation. This was accompanied early cell death outer retina, which later points, thinning. A loss small capillaries hypoxia observed months, indicating inner blood‒retinal barrier (BRB) alteration but without retina. Moreover, activated microglial cells invaded entire retina surrounded vessels, suggesting death. also triggered persistent invasion pigment epithelium macrophages, contributing BRB disruption. study highlights long-lasting inflammatory mechanisms development demonstrates relevance this model investigate human pathology.

Язык: Английский

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Locomotor and gait changes in the LPS model of neuroinflammation are correlated with inflammatory cytokines in blood and brain

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

Опубликована: Окт. 8, 2024

Lipopolysaccharide (LPS) challenge in mice has been used to identify the mechanisms and therapeutics for neuroinflammation. In this study, we aimed comprehensively evaluate behavioral changes including locomotion, exploration, memory, correlating them with a panel of thirteen inflammatory cytokines both blood brain.We found that acute LPS administration (0.83 mg/Kg i.p.) reduced body weight, food intake, glucose levels compared saline-injected mice, concomitant decreased activity home cage monitoring. Locomotion was significantly Open Field, Introduced Object, Y-Maze tests. Decreased exploratory behavior Object tests noticed, by measuring number arms explored object interaction time, respectively. Additionally, rotarod, led significant decrease distance achieved, while MouseWalker, reduction average velocity.LPS induced microglia ramification index motor cortex striatum, surprisingly observed cortex.The concentrations were altered, only CXCL1, CCL22, CCL17, G-CSF, IL-12p40 changed brain. Correlations between cytokine brain found, most notably CCL17 CCL22. TGFβ one negative correlations other cytokines. also disclosed, especially IL-6 negatively IL-10.In summary, our study employing revealed comprehensive profile alterations alongside levels, peripheral tissue. These findings contribute deeper understanding interplay inflammation behavior, possible implications identifying prognostics therapeutic targets neuroinflammatory conditions.

Язык: Английский

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Chronic activation of a negative engram induces behavioral and cellular abnormalities

eLife, Год журнала: 2024, Номер 13

Опубликована: Апрель 17, 2024

Negative memories engage a brain and body-wide stress response in humans that can alter cognition behavior. Prolonged responses induce maladaptive cellular, circuit, systems-level changes lead to pathological states corresponding disorders which mood memory are affected. However, it is unclear if repeated activation of cells processing negative induces similar phenotypes mice. In this study, we used an activity-dependent tagging method access neuronal ensembles assess their molecular characteristics. Sequencing engrams mice revealed positive (male-to-female exposure) (foot shock) upregulated genes linked anti- pro-inflammatory responses, respectively. To investigate the impact persistent engrams, chemogenetically activated them ventral hippocampus over 3 months conducted anxiety memory-related tests. engram increased behaviors both 6- 14-month-old mice, reduced spatial working older impaired fear extinction younger heightened generalization age groups. Immunohistochemistry microglial astrocytic structure number hippocampus. summary, lasting cellular behavioral abnormalities offering insights into effects chronic thinking-like on human health.

Язык: Английский

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