Phagocytosis in the Brain: Homeostasis and Disease

Frontiers in Immunology, Год журнала: 2019, Номер 10

Опубликована: Апрель 16, 2019

Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, diseased states. Phagocytosis is a highly complex process that specialized for uptake removal opsonized non-opsonized targets, such as pathogens, apoptotic cells, cellular debris. While role mediating classical innate adaptive immune responses has been known decades, it now appreciated also critical throughout early neural initiating repair mechanisms. As such, modulating phagocytic processes provided unexplored avenues with intent developing novel therapeutics promote regeneration CNS. Here, we review functional consequences plays both healthy CNS, summarize how contributes pathophysiological mechanisms involved injury repair.

Язык: Английский

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Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice

Nature Neuroscience, Год журнала: 2020, Номер 24(2), С. 214 - 224

Опубликована: Дек. 22, 2020

The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain associated with an increased risk schizophrenia. To investigate this genetic finding address how shapes circuits vivo, here, we generated a mouse model primate-lineage-specific isoforms C4, human and/or C4B. Human bound synapses more efficiently than (but not C4B) rescued visual system refinement deficits C4 knockout mice. Intriguingly, mice without had normal numbers cortical synapses, which suggests that required for developmental pruning. However, overexpressing reduced synapse density, microglial engulfment altered behavior. These results suggest C4A-mediated elimination abnormal Understanding pathological overpruning mechanisms has important therapeutic implications disease conditions such as

Язык: Английский

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Microglial Phagocytosis of Newborn Cells Is Induced by Endocannabinoids and Sculpts Sex Differences in Juvenile Rat Social Play

Neuron, Год журнала: 2019, Номер 102(2), С. 435 - 449.e6

Опубликована: Фев. 28, 2019

Язык: Английский

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Transcriptional signature in microglia associated with Aβ plaque phagocytosis

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Май 21, 2021

Abstract The role of microglia cells in Alzheimer’s disease (AD) is well recognized, however their molecular and functional diversity remain unclear. Here, we isolated amyloid plaque-containing (using labelling with methoxy-XO4, XO4 + ) non-containing (XO4 − from an AD mouse model. Transcriptomics analysis identified different transcriptional trajectories ageing mice. microglial transcriptomes demonstrated dysregulated expression genes associated late onset AD. We further showed that the program mice present a subset human brains individuals displayed signatures accelerated contained more intracellular post-synaptic material than microglia, despite reduced active synaptosome phagocytosis. HIF1α as potentially regulating phagocytosis vitro using primary BV2 cells. Together, these findings provide insight into mechanisms underpinning

Язык: Английский

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Biomimetic Nanoerythrosome‐Coated Aptamer–DNA Tetrahedron/Maytansine Conjugates: pH‐Responsive and Targeted Cytotoxicity for HER2‐Positive Breast Cancer

Advanced Materials, Год журнала: 2022, Номер 34(46)

Опубликована: Янв. 22, 2022

DNA materials have emerged as potential nanocarriers for targeted cancer therapy to precisely deliver cargos with specific purposes. The short half-life and low bioavailability of due their interception by the reticuloendothelial system blood clearance further limit clinical translation. This study employs an HER2-targeted DNA-aptamer-modified tetrahedron (HApt-tFNA) a drug delivery system, combines maytansine (DM1) develop HApt-DNA tetrahedron/DM1 conjugate (HApt-tFNA@DM1, HTD, HApDC) HER2-positive cancer. To optimize pharmacokinetics tumor-aggregation biomimetic camouflage is applied embed HTD. constructed merging erythrocyte membrane pH-responsive functionalized synthetic liposomes, thus excellent performance tumor-stimulated release. hybrid erythrosome-based nanoparticles show better inhibition than other formulations exhibit superior biosafety. With strengths precise delivery, increased loading, sensitive tumor probing, prolonged circulation time, HApDC represents promising nanomedicine treat tumors. Notably, this developsa dual-targeting nanoparticle combining pH-sensitive HApDC, initiating important step toward development application DNA-based medicine cell in treatment biological applications.

Язык: Английский

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Complement Signals Determine Opposite Effects of B Cells in Chemotherapy-Induced Immunity

Cell, Год журнала: 2020, Номер 180(6), С. 1081 - 1097.e24

Опубликована: Март 1, 2020

Язык: Английский

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The good, the bad, and the opportunities of the complement system in neurodegenerative disease

Journal of Neuroinflammation, Год журнала: 2020, Номер 17(1)

Опубликована: Ноя. 25, 2020

Abstract The complement cascade is a critical effector mechanism of the innate immune system that contributes to rapid clearance pathogens and dead or dying cells, as well contributing extent limit inflammatory response. In addition, some early components this have been clearly shown play beneficial role in synapse elimination during development nervous system, although excessive complement-mediated synaptic pruning adult injured brain may be detrimental multiple neurogenerative disorders. While many these later studies mouse models, observations consistent with notion reported human postmortem examination tissue. Increasing awareness distinct roles C1q, initial recognition component classical pathway, are independent rest cascade, relationship other signaling pathways inflammation (in periphery central system), highlights need for thorough understanding molecular entities facilitate successful therapeutic design, including target identification, disease stage treatment, delivery specific neurologic Here, we review evidence both effects activation products neurodegenerative Evidence requisite co-factors diverse consequences reviewed, recent support possibility pharmacological approaches suppress chronic inflammation, while preserving components, slow progression disease.

Язык: Английский

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Macrophages at the interface of the co-evolving cancer ecosystem

Cell, Год журнала: 2023, Номер 186(8), С. 1627 - 1651

Опубликована: Март 15, 2023

Язык: Английский

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Microglial phagocytosis of neurons in neurodegeneration, and its regulation

Journal of Neurochemistry, Год журнала: 2021, Номер 158(3), С. 621 - 639

Опубликована: Фев. 20, 2021

There is growing evidence that excessive microglial phagocytosis of neurons and synapses contributes to multiple brain pathologies. RNA-seq genome-wide association (GWAS) studies have linked phagocytic genes neurodegenerative diseases, knock-out has been found protect against neurodegeneration in animal models, suggesting neurodegeneration. Here, we review recent live causes models Alzheimer's disease other tauopathies, Parkinson's disease, frontotemporal dementias, sclerosis, retinal degeneration induced by ischaemia, infection or ageing. We also factors regulating neurons, including: nucleotides, frackalkine, phosphatidylserine, calreticulin, UDP, CD47, sialylation, complement, galectin-3, Apolipoprotein E, receptors, Siglec cytokines, epigenetics expression profile. Some these may be potential treatment targets prevent mediated synapses.

Язык: Английский

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Innate immunity at the crossroads of healthy brain maturation and neurodevelopmental disorders

Nature reviews. Immunology, Год журнала: 2021, Номер 21(7), С. 454 - 468

Опубликована: Янв. 21, 2021

Язык: Английский

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