15(S)-Lipoxygenase-1 associates with neutral lipid droplets in macrophage foam cells: evidence of lipid droplet metabolism

Abstract Background Disease-associated microglia (DAMs), that surround beta-amyloid plaques, represent a transcriptionally-distinct microglial profile in Alzheimer’s disease (AD). Activation of DAMs is dependent on triggering receptor expressed on myeloid cells 2 (TREM2) in mouse models and the AD TREM2-R47H risk variant reduces microglial activation and plaque association in human carriers. Interestingly, TREM2 has also been identified as a microglial lipid-sensor, and recent data indicates lipid droplet accumulation in aged microglia, that is in turn associated with a dysfunctional proinflammatory phenotype. However, whether lipid droplets (LDs) are present in human microglia in AD and how the R47H mutation affects this remains unknown. Methods To determine the impact of the TREM2 R47H mutation on human microglial function in vivo, we transplanted wild-type and isogenic TREM2-R47H iPSC-derived microglial progenitors into our recently developed chimeric Alzheimer mouse model. At 7 months of age scRNA-seq and histological analyses were performed. Results Here we report that the transcriptome of human wild-type TREM2 and isogenic TREM2-R47H DAM xenografted microglia (xMGs), isolated from chimeric AD mice, closely resembles that of human atherosclerotic foam cells. In addition, much like foam cells, plaque-bound xMGs are highly enriched in lipid droplets. Somewhat surprisingly and in contrast to a recent in vitro study, TREM2-R47H mutant xMGs exhibit an overall reduction in the accumulation of lipid droplets in vivo. Notably, TREM2-R47H xMGs also show overall reduced reactivity to plaques, including diminished plaque-proximity, reduced CD9 expression, and lower secretion of plaque-associated APOE. Conclusions Altogether, these results indicate lipid droplet accumulation occurs in human DAM xMGs in AD, but is reduced in TREM2-R47H DAM xMGs, as it occurs secondary to TREM2-mediated changes in plaque proximity and reactivity.

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Foam Cell Macrophages in Tuberculosis

Frontiers in Immunology ◽

10.3389/fimmu.2021.775326 ◽

2021 ◽

Vol 12 ◽

Author(s):

Pooja Agarwal ◽

Siamon Gordon ◽

Fernando O. Martinez

Keyword(s):

Mycobacterium Tuberculosis ◽

Lipid Droplet ◽

Immune Cells ◽

Lipid Droplets ◽

Foam Cell ◽

Cell Formation ◽

Foam Cells ◽

Metabolic Changes ◽

Foam Cell Formation ◽

Lipid Contents

Mycobacterium tuberculosis infects primarily macrophages in the lungs. Infected macrophages are surrounded by other immune cells in well organised structures called granulomata. As part of the response to TB, a type of macrophage loaded with lipid droplets arises which we call Foam cell macrophages. They are macrophages filled with lipid laden droplets, which are synthesised in response to increased uptake of extracellular lipids, metabolic changes and infection itself. They share the appearance with atherosclerosis foam cells, but their lipid contents and roles are different. In fact, lipid droplets are immune and metabolic organelles with emerging roles in Tuberculosis. Here we discuss lipid droplet and foam cell formation, evidence regarding the inflammatory and immune properties of foam cells in TB, and address gaps in our knowledge to guide further research.

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Th-P15:4 The lipid droplet surface protein adipophilin inhibits cholesterol clearance from human macrophage foam cells

Atherosclerosis Supplements ◽

10.1016/s1567-5688(06)81964-1 ◽

2006 ◽

Vol 7 (3) ◽

pp. 492

Author(s):

C.M. Quinn ◽

L. Kritharides ◽

W. Jessup

Keyword(s):

Lipid Droplet ◽

Surface Protein ◽

Foam Cells ◽

Droplet Surface ◽

Human Macrophage ◽

Macrophage Foam Cells

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Recruitment of Peroxin14 to lipid droplets affects triglyceride storage in Drosophila

10.1101/2021.07.02.450950 ◽

2021 ◽

Author(s):

Matthew Anderson-Baron ◽

Kazuki Ueda ◽

Julie Haskins ◽

Sarah C Hughes ◽

Andrew Simmonds

Keyword(s):

Neutral Lipid ◽

Lipid Droplet ◽

Functional Role ◽

Lipid Droplets ◽

Droplet Surface ◽

Lipid Homeostasis ◽

Cellular Lipid ◽

Peroxisome Biogenesis ◽

Drosophila Cells

The activity of multiple organelles must be coordinated to ensure cellular lipid homeostasis. This includes the peroxisomes which metabolise certain lipids and lipid droplets which act as neutral lipid storage centres. Direct organellar contact between peroxisomes and lipid droplets has been observed, and interaction between proteins associated with the membranes of these organelles has been shown, but the functional role of these interactions is not clear. In Drosophila cells, we identified a novel localization of a subset of three transmembrane Peroxin proteins (Peroxin3, Peroxin13, and Peroxin14), normally required for peroxisome biogenesis, to newly formed lipid droplets. This event was not linked to significant changes in peroxisome size or number, nor was recruitment of other Peroxin proteins or mature peroxisomes observed. The presence of these Peroxin proteins at lipid droplets influences their function as changes in the relative levels of Peroxin14 associated with the lipid droplet surface directly affected the presence of regulatory perilipin and lipases with corresponding effects on triglyceride storage.

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