Dataset Information

Differential Phagocytic Properties of CD45low Microglia and CD45high Brain Mononuclear Phagocytes-Activation and Age-Related Effects.

ABSTRACT: In the central nervous system (CNS), microglia are innate immune mononuclear phagocytes (CNS MPs) that can phagocytose infectious particles, apoptotic cells, neurons, and pathological protein aggregates, such as A? in Alzheimer's disease (AD). While CD11b+CD45low microglia account for the majority of CNS MPs, a small population of CD11b+CD45high CNS MPs is also recognized in AD that surround A? plaques. These transcriptionally and pathologically unique CD45high cells have unclear origin and undefined phagocytic characteristics. We have comprehensively validated rapid flow cytometric assays of bulk-phase and amyloid ? fibril (fA?) phagocytosis and applied these to study acutely isolated CNS MPs. Using these methods, we provide novel insights into differential abilities of CD11b+ CD45low and CD45high CNS MPs to phagocytose macroparticles and fA? under normal, acute, and chronic neuroinflammatory states. CD45high CNS MPs also highly upregulate TREM2, CD11c, and several disease-associated microglia signature genes and have a higher phagocytic capacity for A? as compared to CD45low microglia in the 5xFAD mouse model of AD that becomes more apparent with aging. Our data suggest an overall pro-phagocytic and protective role for CD11b+CD45high CNS MPs in neurodegeneration, which if promoted, could be beneficial.

SUBMITTER: Rangaraju S

PROVIDER: S-EPMC5840283 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Differential Phagocytic Properties of CD45low Microglia and CD45high Brain Mononuclear Phagocytes-Activation and Age-Related Effects.

Rangaraju Srikant S Raza Syed Ali SA Li Noel Xiang'An NX Betarbet Ranjita R Dammer Eric B EB Duong Duc D Lah James J JJ Seyfried Nicholas T NT Levey Allan I AI

Frontiers in immunology 20180302

In the central nervous system (CNS), microglia are innate immune mononuclear phagocytes (CNS MPs) that can phagocytose infectious particles, apoptotic cells, neurons, and pathological protein aggregates, such as Aβ in Alzheimer's disease (AD). While CD11b+CD45low microglia account for the majority of CNS MPs, a small population of CD11b+CD45high CNS MPs is also recognized in AD that surround Aβ plaques. These transcriptionally and pathologically unique ...[more]

PMID: 29552013

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Project description:BackgroundDietary high salt (HS) is a leading risk factor for mortality and morbidity. Serum sodium transiently increases postprandially but can also accumulate at sites of inflammation affecting differentiation and function of innate and adaptive immune cells. Here, we focus on how changes in extracellular sodium, mimicking alterations in the circulation and tissues, affect the early metabolic, transcriptional, and functional adaption of human and murine mononuclear phagocytes.MethodsUsing Seahorse technology, pulsed stable isotope-resolved metabolomics, and enzyme activity assays, we characterize the central carbon metabolism and mitochondrial function of human and murine mononuclear phagocytes under HS in vitro. HS as well as pharmacological uncoupling of the electron transport chain under normal salt is used to analyze mitochondrial function on immune cell activation and function (as determined by Escherichia coli killing and CD4+ T cell migration capacity). In 2 independent clinical studies, we analyze the effect of a HS diet during 2 weeks (URL: http://www.clinicaltrials.gov. Unique identifier: NCT02509962) and short-term salt challenge by a single meal (URL: http://www.clinicaltrials.gov. Unique identifier: NCT04175249) on mitochondrial function of human monocytes in vivo.ResultsExtracellular sodium was taken up into the intracellular compartment, followed by the inhibition of mitochondrial respiration in murine and human macrophages. Mechanistically, HS reduces mitochondrial membrane potential, electron transport chain complex II activity, oxygen consumption, and ATP production independently of the polarization status of macrophages. Subsequently, cell activation is altered with improved bactericidal function in HS-treated M1-like macrophages and diminished CD4+ T cell migration in HS-treated M2-like macrophages. Pharmacological uncoupling of the electron transport chain under normal salt phenocopies HS-induced transcriptional changes and bactericidal function of human and murine mononuclear phagocytes. Clinically, also in vivo, rise in plasma sodium concentration within the physiological range reversibly reduces mitochondrial function in human monocytes. In both a 14-day and single meal HS challenge, healthy volunteers displayed a plasma sodium increase of [Formula: see text] and [Formula: see text] respectively, that correlated with decreased monocytic mitochondrial oxygen consumption.ConclusionsOur data identify the disturbance of mitochondrial respiration as the initial step by which HS mechanistically influences immune cell function. Although these functional changes might help to resolve bacterial infections, a shift toward proinflammation could accelerate inflammatory cardiovascular disease.

Project description:IntroductionMultiple object tracking (MOT) is a powerful paradigm for measuring sustained attention. Although previous fMRI studies have delineated the brain activation patterns associated with tracking and documented reduced tracking performance in aging, age-related effects on brain activation during MOT have not been characterized. In particular, it is unclear if the task-related activation of different brain networks is correlated, and also if this coordination between activations within brain networks shows differential effects of age.MethodsWe obtained fMRI data during MOT at two load conditions from a group of younger (n = 25, mean age = 24.4 ± 5.1 years) and older (n = 21, mean age = 64.7 ± 7.4 years) healthy adults. Using a combination of voxel-wise and independent component analysis, we investigated age-related differences in the brain network activation. In order to explore to which degree activation of the various brain networks reflect unique and common mechanisms, we assessed the correlations between the brain networks' activations.ResultsBehavioral performance revealed an age-related reduction in MOT accuracy. Voxel and brain network level analyses converged on decreased load-dependent activations of the dorsal attention network (DAN) and decreased load-dependent deactivations of the default mode networks (DMN) in the old group. Lastly, we found stronger correlations in the task-related activations within DAN and within DMN components for younger adults, and stronger correlations between DAN and DMN components for older adults.ConclusionUsing MOT as means for measuring attentional performance, we have demonstrated an age-related attentional decline. Network-level analysis revealed age-related alterations in network recruitment consisting of diminished activations of DAN and diminished deactivations of DMN in older relative to younger adults. We found stronger correlations within DMN and within DAN components for younger adults and stronger correlations between DAN and DMN components for older adults, indicating age-related alterations in the coordinated network-level activation during attentional processing.

Dataset Information

Differential Phagocytic Properties of CD45low Microglia and CD45high Brain Mononuclear Phagocytes-Activation and Age-Related Effects.

Publications

Differential Phagocytic Properties of CD45<sup>low</sup> Microglia and CD45<sup>high</sup> Brain Mononuclear Phagocytes-Activation and Age-Related Effects.

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