Neutrophil microvesicles are increased by high-fat over-feeding and enhance monocyte recruitment to endothelial cells under disturbed flow

Ward, Ben; Gomez, Ingrid; Willis, Jess; Woods, Rachel; Parry, Siôn A; Hulston, Carl J.; Evans, Paul C.; Ridger, Victoria

doi:10.1016/j.atherosclerosis.2017.06.398

Cited by 2 publications

(1 citation statement)

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“…Together, these lead to disruption of blood-brain barrier (BBB) homeostasis, causing increased BBB permeability via activation of endothelial cells and pericytes, key components and regulators of BBB [47]. Upon activation of WD-induced immune stimuli, endothelial cells can produce proinflammatory cytokines to attract peripheral myeloid cells including monocytes and neutrophils to the “injury” site [48–51]. Pericytes can also be activated to release proinflammatory cytokines or reactive oxygen species that further exacerbate BBB disruption by destabilizing tight junction proteins [52].…”

Section: Discussionmentioning

confidence: 99%

Transcriptome profiling of brain myeloid cells revealed activation of Itgal, Trem1, and Spp1 in western diet-induced obesity

Yang

Graham

Reagan

et al. 2019

J Neuroinflammation

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Background Environmental factors are critical in the development of age-related cognitive decline and dementia. A western diet (WD) can cause nutrient deficiency and inflammation that could impact cognition directly. It is increasingly recognized that innate immune responses by brain myeloid cells, such as resident microglia, and infiltrating peripheral monocytes/macrophages may represent an essential link between a WD, cognitive decline, and dementia. Our previous data demonstrated that chronic consumption of a WD induced inflammation through brain myeloid cells in aging mice and a mouse model of Alzheimer’s disease (AD). However, the subtypes of myeloid cells that contribute to the WD-induced inflammation remain unclear. Methods C57BL/6J (B6), myeloid cell reporter mice (B6. Ccr2 RFP/+ Cx3cr1 GFP/+ ), and Ccr2 -deficient mice (B6. Ccr2 RFP/RFP ) were fed a WD or a control chow diet (CD) from 2 to 6 or 12 months of age. CD11b+CD45 lo and CD11b+CD45 hi cells from WD- and CD-fed B6 or Ccr2 -deficient mice were characterized using flow cytometry, RNA-sequencing, and immunofluorescence. Results Ccr2 ::RFP expressing myeloid cells were significantly increased in brains of WD- compared to CD-fed mice, but were not elevated in Ccr2 -deficient WD-fed mice. The percent of CD11b+CD45 hi cells was significantly increased in WD- compared to CD-fed mice. Comparison of RNA-sequencing data with immune cell data in ImmGen supports that CD11b+CD45 hi cells from WD-fed mice are enriched for peripheral monocytes and neutrophils. Ingenuity pathway analysis predicted these cells elicit proinflammatory responses that may be damaging to the brain. Using stringent criteria for gene expression levels between CD11b+CD45 hi and CD11b+CD45 lo cells, we identified approximately 70 genes that we predict are uniquely expressed in infiltrating cells, including Itgal , Trem1 , and Spp1 (osteopontin, OPN ) . Finally, we show a significantly greater number of OPN+IBA1– cells in WD- compared to CD-fed mice that we propose are activated neutrophils based on ImmGen data. OPN+IBA1– cells are not significantly increased in Ccr2 -deficient WD-fed mice. Conclusions These data further support the model that peripheral myeloid cells enter the brain in response to diet-induced obesity. Elucidating their contribution to age-related cognitive decline and age-related neurodegenerative diseases should offer new avenues for therapeutic intervention ...

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Section: Discussionmentioning

confidence: 99%

Transcriptome profiling of brain myeloid cells revealed activation of Itgal, Trem1, and Spp1 in western diet-induced obesity

Yang

Graham

Reagan

et al. 2019

J Neuroinflammation

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MPO (Myeloperoxidase) Reduces Endothelial Glycocalyx Thickness Dependent on Its Cationic Charge

Manchanda

Kolářová

Kerkenpaß

et al. 2018

ATVB

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Objective- The leukocyte heme-enzyme MPO (myeloperoxidase) exerts proinflammatory effects on the vascular system primarily linked to its catalytic properties. Recent studies have shown that MPO, depending on its cationic charge, mediates neutrophil recruitment and activation. Here, we further investigated MPO's extracatalytic properties and its effect on endothelial glycocalyx (EG) integrity. Approach and Results- In vivo staining of murine cremaster muscle vessels with Alcian Blue 8GX provided evidence of an MPO-dependent decrease in anionic charge of the EG. MPO binding to the glycocalyx was further characterized using Chinese hamster ovary cells and its glycosaminoglycan mutants-pgsA-745 (mutant Chinese hamster ovary cells lacking heparan sulfate and chondroitin sulfate glycosaminoglycan) and pgsD-677 (mutant Chinese hamster ovary cells lacking heparan sulfate glycosaminoglycan), which revealed heparan sulfate as the main mediator of MPO binding. Further, EG integrity was assessed in terms of thickness using intravital microscopy of murine cremaster muscle. A significant reduction in EG thickness was observed on infusion of catalytically active MPO, as well as mutant inactive MPO and cationic polymer polylysine. Similar effects were also observed in wild-type mice after a local inflammatory stimulus but not in MPO-knockout mice. The reduction in EG thickness was reversed after removal of vessel-bound MPO, suggesting a possible physical collapse of the EG. Last, experiments with in vivo neutrophil depletion revealed that MPO also induced neutrophil-mediated shedding of the EG core protein, Sdc1 (syndecan-1). Conclusions- These findings provide evidence that MPO, via ionic interaction with heparan sulfate side chains, can cause neutrophil-dependent Sdc1 shedding and collapse of the EG structure.

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Neutrophil microvesicles are increased by high-fat over-feeding and enhance monocyte recruitment to endothelial cells under disturbed flow

Cited by 2 publications

References 0 publications

Transcriptome profiling of brain myeloid cells revealed activation of Itgal, Trem1, and Spp1 in western diet-induced obesity

Transcriptome profiling of brain myeloid cells revealed activation of Itgal, Trem1, and Spp1 in western diet-induced obesity

MPO (Myeloperoxidase) Reduces Endothelial Glycocalyx Thickness Dependent on Its Cationic Charge

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