Foam cell

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Foam cell
Histopathology of cholesterolosis, with annotated foam cell.jpg
Foam cells (one indicated by arrows) visible in the finger-like projections into the gallbladder lumen in a case of cholesterolosis
Details
Precursor monocyte-derived macrophage
Identifiers
MeSH D005487
FMA 83586
Anatomical terms of microanatomy

Foam cells, also called lipid-laden macrophages, are a type of cell that contain cholesterol. These can form a plaque that can lead to atherosclerosis and trigger myocardial infarction and stroke. [1] [2] [3]

Contents

Foam cells are fat-laden cells with a M2 macrophage-like phenotype. They contain low density lipoproteins (LDL) and can only be truly detected by examining a fatty plaque under a microscope after it is removed from the body. [4] They are named because the lipoproteins give the cell a foamy appearance. [5]

Despite the connection with cardiovascular diseases they might not be inherently dangerous. [6]

Some foam cells are derived from smooth muscle cells and present a limited macrophage-like phenotype. [7] [8] [9]

Formation

Foam cell formation is triggered by a number of factors including the uncontrolled uptake of modified low density lipoproteins (LDL), the upregulation of cholesterol esterification and the impairment of mechanisms associated with cholesterol release. [2] Foam cells are formed when circulating monocyte-derived cells are recruited to the atherosclerotic lesion site or fat deposits in the blood vessel walls. Recruitment is facilitated by the molecules P-selectin and E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). [10]

Monocytes are then able to penetrate the arterial wall as a result of impaired endothelial integrity which increases permeability. Once in the sub endothelium space, inflammation processes induce the differentiation of monocytes into mature macrophages. [10] Macrophages are then able to internalize modified lipoproteins like βVLDL (beta very low density lipoprotein), AcLDL (acetylated low density lipoprotein) and OxLDL (oxidized low density lipoprotein) through their binding to the scavenger receptors (SRs) such as CD36 and SR-A on the macrophage surface. [2] These scavenger receptors act as "Pattern recognition receptors" (PRR's) on macrophages and are responsible for recognizing and binding to oxLDL, which in turn promotes the formation of foam cells through internalization of these lipoproteins. [11]

Coated-pit endocytosis, phagocytosis and pinocytosis are also responsible for lipoprotein internalization. [12] Once internalized, scavenged lipoproteins are transported to endosomes or lysosomes for degradation, whereby the cholesteryl esters (CE) are hydrolyzed to unesterified free cholesterol (FC) by lysosomal acid lipase (LPL). Free cholesterol is transported to the endoplasmic reticulum where it is re-esterified by ACAT1 (acyl-CoA: cholesterol acyltransferase 1) and subsequently stored as cytoplasmic liquid droplets. These droplets are responsible for the foamy appearance of the macrophage and thus the name of foam cells. [2] At this point, foam cells can either be degraded though the de-esterification and secretion of cholesterol, or can further promote foam cell development and plaque formation – a process that is dependent on the balance of free cholesterol and esterified cholesterol. [2]

Composition

Low-density lipoprotein (LDL) cholesterol (LDL-C — also known as “bad” cholesterol) and particularly modified forms of LDL cholesterol such as oxidized, glycated, or acetylated LDL, is contained by a foam cell - a marker of atherosclerosis. [3] The uptake of LDL-C alone does not cause foam cell formation; however, the co-internalization of LDL-C with modified LDL in macrophages can result in foam cell development. Modified LDL affects the intracellular trafficking and metabolism of native LDL, such that not all LDL need to be modified for foam cell formation when LDL levels are high. [12]

The maintenance of foam cells and the subsequent progression of plaque build-up is caused by the secretion of chemokines and cytokines from macrophages and foam cells. Foam cells secrete pro-inflammatory cytokines such as interleukins: IL-1, IL-6; tumour necrosis factor (TNF); chemokines: chemokines ligand 2, CCL5, CXC-chemokine ligand 1 (CXCL1); as well as macrophage retention factors. [11] Macrophages within the atherosclerotic legion area have a decreased ability to migrate, which further promotes plaque formation as they are able to secrete cytokines, chemokines, reactive oxygen species (ROS) and growth factors that stimulate modified lipoprotein uptake and vascular smooth muscle cell (VSMC) proliferation. [10] [6] [13] VSMC can also accumulate cholesteryl esters. [6]

In chronic hyperlipidemia, lipoproteins aggregate within the intima of blood vessels and become oxidized by the action of oxygen free radicals generated either by macrophages or endothelial cells. The macrophages engulf oxidized low-density lipoproteins (LDLs) by endocytosis via scavenger receptors, which are distinct from LDL receptors. The oxidized LDL accumulates in the macrophages and other phagocytes, which are then known as foam cells. [14] Foam cells form the fatty streaks of the plaques of atheroma in the tunica intima of arteries.

Foam cells are not dangerous as such, but can become a problem when they accumulate at particular foci thus creating a necrotic centre of atherosclerosis. If the fibrous cap that prevents the necrotic centre from spilling into the lumen of a vessel ruptures, a thrombus can form which can lead to emboli occluding smaller vessels. The occlusion of small vessels results in ischemia, and contributes to stroke and myocardial infarction, two of the leading causes of cardiovascular-related death. [6] However, during the early stages of their pathogenesis, foam cells have also been observed to adopt a pro-fibrotic phenotype in which they increase the stability of a nascent plaque through the up-regulation of the Liver X Receptor (LXR) pathway and the increased expression of extra-cellular matrix (ECM) associated genes. [15]

Foam cells are very small in size and can only be truly detected by examining a fatty plaque under a microscope after it is removed from the body, or more specifically from the heart. Detection usually involves the staining of sections of aortic sinus or artery with Oil Red O (ORO) followed by computer imaging and analysis; or from Nile Red Staining. In addition, fluorescent microscopy or flow cytometry can be used to detect OxLDL uptake when OxLDL has been labeled with 1,1′-dioctadecyl-3,3,3′3′-tetra-methylindocyanide percholorate (DiI-OxLDL). [4]

Autoimmunity occurs when the body starts attacking itself. The link between atherosclerosis and autoimmunity is plasmacytoid dendritic cells (pDCs). PDCs contribute to the early stages of the formation of atherosclerotic lesions in the blood vessels by releasing large quantities of type 1 interferons (INF). Stimulation of pDCs leads to an increase of macrophages present in plaques. However, during later stages of lesion progression, pDCs have been shown to have a protective effect by activating T cells and Treg function; leading to disease suppression. [16]

Degradation

Foam cell degradation or more specifically the breakdown of esterified cholesterols, is facilitated by a number of efflux receptors and pathways. Esterified cholesterol from cytoplasmic liquid droplets are once again hydrolyzed to free cholesterol by acid cholesterol esterase. Free cholesterol can then be secreted from the macrophage by the efflux to ApoA1 and ApoE discs via the ABCA1 receptor. This pathway is usually used by modified or pathological lipoproteins like AcLDL, OxLDL and βVLDL. FC can also be transported to a recycling compartment through the efflux to ApoA1 containing HDLs (high density lipoproteins) via aqueous diffusion or transport through the SR-B1 or ABCG1 receptors. While this pathway can also be used by modified lipoproteins, LDL derived cholesterol can only use this pathway to excrete FC. The differences in excretory pathways between types of lipoproteins is mainly a result of the cholesterol being segregated into different areas. [2] [6] [17]

Infectious diseases

Foamy macrophages are also found in diseases caused by pathogens that persist in the body, such as Chlamydia , Toxoplasma , or Mycobacterium tuberculosis . In tuberculosis (TB), bacterial lipids disable macrophages from pumping out excess LDL, causing them to turn into foam cells around the TB granulomas in the lung. The cholesterol forms a rich food source for the bacteria. As the macrophages die, the mass of cholesterol in the center of the granuloma becomes a cheesy substance called caseum. [18]

Other conditions

Foam cells may form around leaked silicone from breast implants. [19] Lipid-laden alveolar macrophages, also known as pulmonary foam cells, are seen in bronchoalveolar lavage specimens in some respiratory diseases. [20]

Related Research Articles

<span class="mw-page-title-main">Cholesterol</span> Sterol biosynthesized by all animal cells

Cholesterol is the principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils.

High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are typically composed of 80–100 proteins per particle. HDL particles enlarge while circulating in the blood, aggregating more fat molecules and transporting up to hundreds of fat molecules per particle.

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Atherosclerosis</span> Form of arteriosclerosis

Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. These lesions may lead to narrowing of the arterial walls due to buildup of atheromatous plaques. At onset there are usually no symptoms, but if they develop, symptoms generally begin around middle age. In severe cases, it can result in coronary artery disease, stroke, peripheral artery disease, or kidney disorders, depending on which body part(s) the affected arteries are located in the body.

<span class="mw-page-title-main">Lipoprotein</span> Biochemical assembly whose purpose is to transport hydrophobic lipid molecules

A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.

A vulnerable plaque is a kind of atheromatous plaque – a collection of white blood cells and lipids in the wall of an artery – that is particularly unstable and prone to produce sudden major problems such as a heart attack or stroke.

Hyperlipidemia is abnormally high levels of any or all lipids or lipoproteins in the blood. The term hyperlipidemia refers to the laboratory finding itself and is also used as an umbrella term covering any of various acquired or genetic disorders that result in that finding. Hyperlipidemia represents a subset of dyslipidemia and a superset of hypercholesterolemia. Hyperlipidemia is usually chronic and requires ongoing medication to control blood lipid levels.

Scavenger receptors are a large and diverse superfamily of cell surface receptors. Its properties were first recorded in 1970 by Drs. Brown and Goldstein, with the defining property being the ability to bind and remove modified low density lipoproteins (LDL). Today scavenger receptors are known to be involved in a wide range of processes, such as: homeostasis, apoptosis, inflammatory diseases and pathogen clearance. Scavenger receptors are mainly found on myeloid cells and other cells that bind to numerous ligands, primarily endogenous and modified host-molecules together with pathogen-associated molecular patterns(PAMPs), and remove them. The Kupffer cells in the liver are particularly rich in scavenger receptors, includes SR-A I, SR-A II, and MARCO.

<span class="mw-page-title-main">LDL receptor</span> Mammalian protein found in Homo sapiens

The low-density lipoprotein receptor (LDL-R) is a mosaic protein of 839 amino acids that mediates the endocytosis of cholesterol-rich low-density lipoprotein (LDL). It is a cell-surface receptor that recognizes apolipoprotein B100 (ApoB100), which is embedded in the outer phospholipid layer of very low-density lipoprotein (VLDL), their remnants—i.e. intermediate-density lipoprotein (IDL), and LDL particles. The receptor also recognizes apolipoprotein E (ApoE) which is found in chylomicron remnants and IDL. In humans, the LDL receptor protein is encoded by the LDLR gene on chromosome 19. It belongs to the low density lipoprotein receptor gene family. It is most significantly expressed in bronchial epithelial cells and adrenal gland and cortex tissue.

<span class="mw-page-title-main">Apolipoprotein B</span> Protein-coding gene in the species Homo sapiens

Apolipoprotein B (ApoB) is a protein that in humans is encoded by the APOB gene. It is commonly used to detect risk of atherosclerotic cardiovascular disease.

<span class="mw-page-title-main">VLDL receptor</span> Protein-coding gene in the species Homo sapiens

The very-low-density-lipoprotein receptor (VLDLR) is a transmembrane lipoprotein receptor of the low-density-lipoprotein (LDL) receptor family. VLDLR shows considerable homology with the members of this lineage. Discovered in 1992 by T. Yamamoto, VLDLR is widely distributed throughout the tissues of the body, including the heart, skeletal muscle, adipose tissue, and the brain, but is absent from the liver. This receptor has an important role in cholesterol uptake, metabolism of apolipoprotein E-containing triacylglycerol-rich lipoproteins, and neuronal migration in the developing brain. In humans, VLDLR is encoded by the VLDLR gene. Mutations of this gene may lead to a variety of symptoms and diseases, which include type I lissencephaly, cerebellar hypoplasia, and atherosclerosis.

Anti-cholesterol is a naturally occurring antibody to cholesterol produced by mammals. This antibody serves a ‘housekeeping’ or protective role for the host animal, helping to protect the animal from harmful forms of cholesterol such as LDL and VLDL.

<span class="mw-page-title-main">Hepatic lipase</span> Mammalian protein found in Homo sapiens

Hepatic lipase (HL), also called hepatic triglyceride lipase (HTGL) or LIPC (for "lipase, hepatic"), is a form of lipase, catalyzing the hydrolysis of triacylglyceride. Hepatic lipase is coded by chromosome 15 and its gene is also often referred to as HTGL or LIPC. Hepatic lipase is expressed mainly in liver cells, known as hepatocytes, and endothelial cells of the liver. The hepatic lipase can either remain attached to the liver or can unbind from the liver endothelial cells and is free to enter the body's circulation system. When bound on the endothelial cells of the liver, it is often found bound to heparan sulfate proteoglycans (HSPG), keeping HL inactive and unable to bind to HDL (high-density lipoprotein) or IDL (intermediate-density lipoprotein). When it is free in the bloodstream, however, it is found associated with HDL to maintain it inactive. This is because the triacylglycerides in HDL serve as a substrate, but the lipoprotein contains proteins around the triacylglycerides that can prevent the triacylglycerides from being broken down by HL.

Blood lipids are lipids in the blood, either free or bound to other molecules. They are mostly transported in a phospholipid capsule, and the type of protein embedded in this outer shell determines the fate of the particle and its influence on metabolism. Examples of these lipids include cholesterol and triglycerides. The concentration of blood lipids depends on intake and excretion from the intestine, and uptake and secretion from cells. Hyperlipidemia is the presence of elevated or abnormal levels of lipids and/or lipoproteins in the blood, and is a major risk factor for cardiovascular disease.

<span class="mw-page-title-main">OLR1</span> Protein-coding gene in the species Homo sapiens

Oxidized low-density lipoprotein receptor 1 also known as lectin-type oxidized LDL receptor 1 (LOX-1) is a protein that in humans is encoded by the OLR1 gene.

<span class="mw-page-title-main">LRP1</span> Mammalian protein found in Homo sapiens

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">MSR1</span> Protein-coding gene in the species Homo sapiens

Macrophage scavenger receptor 1, also known as MSR1, is a protein which in humans is encoded by the MSR1 gene. MSR1 has also been designated CD204.

The chronic endothelial injury hypothesis is one of two major mechanisms postulated to explain the underlying cause of atherosclerosis and coronary heart disease (CHD), the other being the lipid hypothesis. Although an ongoing debate involving connection between dietary lipids and CHD sometimes portrays the two hypotheses as being opposed, they are in no way mutually exclusive. Moreover, since the discovery of the role of LDL cholesterol (LDL-C) in the pathogenesis of atherosclerosis, the two hypotheses have become tightly linked by a number of molecular and cellular processes.

<span class="mw-page-title-main">13-Hydroxyoctadecadienoic acid</span> Chemical compound

13-Hydroxyoctadecadienoic acid (13-HODE) is the commonly used term for 13(S)-hydroxy-9Z,11E-octadecadienoic acid (13(S)-HODE). The production of 13(S)-HODE is often accompanied by the production of its stereoisomer, 13(R)-hydroxy-9Z,11E-octadecadienoic acid (13(R)-HODE). The adjacent figure gives the structure for the (S) stereoisomer of 13-HODE. Two other naturally occurring 13-HODEs that may accompany the production of 13(S)-HODE are its cis-trans (i.e., 9E,11E) isomers viz., 13(S)-hydroxy-9E,11E-octadecadienoic acid (13(S)-EE-HODE) and 13(R)-hydroxy-9E,11E-octadecadienoic acid (13(R)-EE-HODE). Studies credit 13(S)-HODE with a range of clinically relevant bioactivities; recent studies have assigned activities to 13(R)-HODE that differ from those of 13(S)-HODE; and other studies have proposed that one or more of these HODEs mediate physiological and pathological responses, are markers of various human diseases, and/or contribute to the progression of certain diseases in humans. Since, however, many studies on the identification, quantification, and actions of 13(S)-HODE in cells and tissues have employed methods that did not distinguish between these isomers, 13-HODE is used here when the actual isomer studied is unclear.

References

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  7. ↑ Li, Yi; Zhu, Huan; Zhang, Qianyu; Han, Ximeng; Zhang, Zhenqian; Shen, Linghong; Wang, Lixin; Lui, Kathy O.; He, Ben; Zhou, Bin (2021-11-23). "Smooth muscle-derived macrophage-like cells contribute to multiple cell lineages in the atherosclerotic plaque". Cell Discovery. 7 (1): 111. doi:10.1038/s41421-021-00328-4. ISSN   2056-5968. PMC   8608914 . PMID   34811358.
  8. ↑ Gui, Yuzhou; Zheng, Hongchao; Cao, Richard Y. (2022). "Foam Cells in Atherosclerosis: Novel Insights Into Its Origins, Consequences, and Molecular Mechanisms". Frontiers in Cardiovascular Medicine. 9: 845942. doi: 10.3389/fcvm.2022.845942 . ISSN   2297-055X. PMC   9043520 . PMID   35498045.
  9. ↑ Pryma, Collin S.; Ortega, Carleena; Dubland, Joshua A.; Francis, Gordon A. (April 2019). "Pathways of smooth muscle foam cell formation in atherosclerosis". Current Opinion in Lipidology. 30 (2): 117–124. doi:10.1097/MOL.0000000000000574. ISSN   0957-9672. PMID   30664015. S2CID   58633787.
  10. 1 2 3 Bobryshev YV, Ivanova EA, Chistiakov DA, Nikiforov NG, Orekhov AN (2016). "Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis". BioMed Research International. 2016: 9582430. doi: 10.1155/2016/9582430 . PMC   4967433 . PMID   27493969.
  11. 1 2 Moore KJ, Sheedy FJ, Fisher EA (October 2013). "Macrophages in atherosclerosis: a dynamic balance". Nature Reviews. Immunology. 13 (10): 709–21. doi:10.1038/nri3520. PMC   4357520 . PMID   23995626.
  12. 1 2 Jones NL, Reagan JW, Willingham MC (March 2000). "The pathogenesis of foam cell formation: modified LDL stimulates uptake of co-incubated LDL via macropinocytosis". Arteriosclerosis, Thrombosis, and Vascular Biology. 20 (3): 773–81. doi: 10.1161/01.atv.20.3.773 . PMID   10712403.
  13. ↑ Shen CM, Mao SJ, Huang GS, Yang PC, Chu RM (December 2001). "Stimulation of smooth muscle cell proliferation by ox-LDL- and acetyl LDL-induced macrophage-derived foam cells". Life Sciences. 70 (4): 443–52. doi:10.1016/s0024-3205(01)01428-x. PMID   11798013.
  14. ↑ Kumar, Abbas; Fausto, Aster (2010). "11". Robbins and Cotran: Pathologic Basis of Disease (Eighth Edition International ed.). Philadelphia: Saunders Elsevier. pp. 500–501. ISBN   978-1-4160-3121-5.
  15. ↑ Newby, Andrew (July 2015). "Foam Cell Formation In Vivo Converts Macrophages to a Pro-Fibrotic Phenotype". PLoS One. 10 (7) – via PMID 26197235.
  16. ↑ Döring Y, Zernecke A (2012). "Plasmacytoid dendritic cells in atherosclerosis". Frontiers in Physiology. 3: 230. doi: 10.3389/fphys.2012.00230 . PMC   3385355 . PMID   22754539.
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  18. ↑ Russell DG, Cardona PJ, Kim MJ, Allain S, Altare F (September 2009). "Foamy macrophages and the progression of the human tuberculosis granuloma". Nature Immunology. 10 (9): 943–8. doi:10.1038/ni.1781. PMC   2759071 . PMID   19692995.
  19. ↑ van Diest, P J; Beekman, W H; Hage, J J (1998). "Pathology of silicone leakage from breast implants". Journal of Clinical Pathology . 51 (7): 493–497. doi:10.1136/jcp.51.7.493. PMC   500799 . PMID   9797723.
  20. ↑ Fessler, Michael B. (2017). "A New Frontier in Immunometabolism. Cholesterol in Lung Health and Disease". Annals of the American Thoracic Society. 14 (Supplement_5): S399–S405. doi:10.1513/AnnalsATS.201702-136AW. ISSN   2329-6933. PMC   5711269 . PMID   29161079.
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