Foam Cells: One Size Doesn’t Fit All

Guerrini, Valentina; Gennaro, Maria Laura

doi:10.1016/j.it.2019.10.002

Cited by 121 publications

(116 citation statements)

References 143 publications

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“…[1][2][3][4] Upon myelin phagocytosis, these cells adopt an enlarged foamy morphology similar to lipid-laden macrophages in atherosclerotic plaques. 1,[5][6][7] In the inflammatory demyelinating disease multiple sclerosis (MS), foam cells in CNS lesions undergo a tri-phasic pattern of polarization. 6 In the first phase, the uptake of myelin leads to a diseasepromoting phenotype associated with secretion of pro-inflammatory cytokines and toxic mediators.…”

Section: Introductionmentioning

confidence: 99%

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275

Zierfuss

Weinhofer

Buda

et al. 2020

Ann Clin Transl Neurol

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Objective: To assess class I-histone deacetylase (HDAC) inhibition on formation of lipid-accumulating, disease-promoting phagocytes upon myelin load in vitro, relevant for neuroinflammatory disorders like multiple sclerosis (MS) and cerebral X-linked adrenoleukodystrophy (X-ALD). Methods: Immunohistochemistry on postmortem brain tissue of acute MS (n = 6) and cerebral ALD (n = 4) cases to analyze activation and foam cell state of phagocytes. RNA-Seq of in vitro differentiated healthy macrophages (n = 8) after sustained myelinloading to assess the metabolic shift associated with foam cell formation. RNA-Seq analysis of genes linked to lipid degradation and export in MS-275-treated human HAP1 cells and RT-qPCR analysis of HAP1 cells knocked out for individual members of class I HDACs or the corresponding enzymatically inactive knock-in mutants. Investigation of intracellular lipid/myelin content after MS-275 treatment of myelin-laden human foam cells. Analysis of disease characteristic very long-chain fatty acid (VLCFA) metabolism and inflammatory state in MS-275-treated X-ALD macrophages. Results: Enlarged foam cells coincided with a pro-inflammatory, lesion-promoting phenotype in postmortem tissue of MS and cerebral ALD patients. Healthy in vitro myelin laden foam cells upregulated genes linked to LXRa/PPARc pathways and mimicked a program associated with tissue repair. Treating these cells with MS-275, amplified this gene transcription program and significantly reduced lipid and cholesterol accumulation and, thus, foam cell formation. In macrophages derived from X-ALD patients, MS-275 improved the disease-associated alterations of VLCFA metabolism and reduced the pro-inflammatory status of these cells. Interpretation: These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.

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Section: Introductionmentioning

confidence: 99%

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275

Zierfuss

Weinhofer

Buda

et al. 2020

Ann Clin Transl Neurol

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mentioning

confidence: 99%

“…In vivo, LD-containing macrophages are most well recognized in atherosclerotic lesions and in tuberculosis 1,14 . More recent work has highlighted the presence of foam cells in active multiple sclerosis, certain cancers, white adipose tissue during obesity, and in bronchoalveolar lavage from individuals suffering from vaping-related lung disease 1 . The ratio of TGs to CEs in LDs in different settings is likely to be important, and there is ongoing discussion regarding whether macrophages that contain CE-rich LDs are universally proinflammatory 15,16 .…”

mentioning

confidence: 99%

Triacylglycerol synthesis enhances macrophage inflammatory function

Castoldi

Monteiro

Bakker

et al. 2020

Preprint

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Macrophages are integral to most tissues. Foam cells, macrophages with lipid droplets (LDs) which are stores of triacylglycerols (TGs) and cholesterol esters (CEs), are found in various disease states 1 . LDs can act as energy stores since TG lipolysis releases fatty acids (FAs) for mitochondrial oxidation (FAO), a process that relies on long-chain FA conversion into acylcarnitines by the enzyme Cpt1a 2 . However, in macrophages, proinflammatory signals result in diminished FAO and increased TG synthesis with LD development 3,4 . We explored the significance of LDs in cells that do not utilize FAO. We show that macrophages stimulated with lipopolysaccharide (LPS) plus interferon-g (IFNg) accumulate TGs in LDs, and long-chain acylcarnitines. In these cells, inhibition of TG synthesis results in diminished LD development, and increased long chain acylcarnitine levels, suggesting that FA fate is balanced between TG and acylcarnitine synthesis. Nevertheless, TG-synthesis is required for inflammatory macrophage function, since its inhibition negatively affects production of proinflammatory IL-1b, IL-6 and PGE2, and phagocytic capacity, and protects against LPS-induced shock in vivo. Failure to make PGE2 is critical for this phenotype, since exogenous PGE2 reverses the anti-inflammatory effects of TG-synthesis inhibition. These findings place LDs in a position of central functional importance in inflammatory macrophages. EJP and ELP are Founders of Rheos Medicines MethodsMice and in vivo experiments C57BL/6 mice (RRID: IMSR_JAX:000664) were from The Jackson Laboratory, and were maintained in specific pathogen-free conditions under protocols approved by the animal care committee of the Regierungspräsidium Freiburg, Germany, in compliance with all relevant ethical regulations. Animals were 6-8 weeks old when used. They were euthanized by carbon dioxide asphyxiation followed by cervical

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“…There are several human disease processes in which dysregulated activity of such a pathway might come into play. The first involves the transformation of macrophages to foam cells filled with lipid inclusions associated with chronic inflammation in a variety of metabolic, infectious, and autoimmune diseases [101]. Foam cells have been shown to have a multitude of roles contributing to pathological immune responses, making them interesting targets for therapeutic development [102].…”

Section: Are There Physiological Orp1l-dependent Cholesterol Transpormentioning

confidence: 99%

“…Our studies suggest a possible role for ORP1L, which is known to be highly expressed in macrophages and to also be up-regulated upon the differentiation of human monocytes into macrophages [107], in pathological accumulation of cholesteryl esters. Interestingly, foam cells are enriched in either triacylglycerol or cholesteryl esters, depending on the inflammatory or pathogen signals driving their differentiation, suggesting that ORP1L may represent a common therapeutic target for diseases capable of inducing formation of foam cells associated with excessive cholesteryl ester production [101]. A second possible scenario where an ORP1L-dependent cholesterol transport pathway might be mis-regulated, involves production of lipid droplets that aberrantly accumulate as a consequence of nutrient and oxidative stress in various cancers [108].…”

Section: Are There Physiological Orp1l-dependent Cholesterol Transpormentioning

confidence: 99%

Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System

Carlin

Manor

2020

IJMS

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In addition to providing invaluable insights to the host response to viral infection, adenovirus continues to be an important model system for discovering basic aspects of cell biology. This is especially true for products of early region three (E3), which have provided the foundation for understanding many new mechanisms regulating intracellular trafficking of host cell proteins involved in the host immune response. Cholesterol homeostasis is vital for proper cellular physiology, and disturbances in cholesterol balance are increasingly recognized as important factors in human disease. Despite its central role in numerous aspects of cellular functions, the mechanisms responsible for delivery of dietary cholesterol to the endoplasmic reticulum, where the lipid metabolic and regulatory machinery reside, remain poorly understood. In this review, we describe a novel intracellular pathway for cholesterol trafficking that has been co-opted by an adenovirus E3 gene product. We describe what is known about the molecular regulation of this pathway, how it might benefit viral replication, and its potential involvement in normal cell physiology. Finally, we make a case that adenovirus has co-opted a cellular pathway that may be dysregulated in various human diseases.

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Foam Cells: One Size Doesn’t Fit All

Cited by 121 publications

References 143 publications

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275

Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275

Triacylglycerol synthesis enhances macrophage inflammatory function

Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System

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