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Foam cell
Foam cells (one indicated by arrows) visible in the finger-like projections into the gallbladder lumen in a case of cholesterolosis
Details
Precursormonocyte-derived macrophage
Identifiers
MeSHD005487
FMA83586
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]

Foam cells are fat-laden cells with an M2 macrophage-like phenotype. They contain low density lipoproteins (LDL) and can be rapidly 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

[edit]

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 a significant component of atherosclerotic lesions, which are formed when circulating monocyte-derived cells are recruited to the atherosclerotic lesion site or fat deposits in the blood vessel walls.[10] 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).[11]

In response to the inflammatory recruitment signals, monocytes are able to penetrate the arterial wall through transendothelial migration, as they can even in healthy arteries. Once in the sub endothelium space, inflammation processes induce the differentiation of monocytes into mature macrophages.[11] 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 (PRRs) 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.[12]

Coated-pit endocytosis, phagocytosis and pinocytosis are also responsible for lipoprotein internalization.[13] 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 lipid 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

[edit]

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.[13]

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.[12] 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.[11][6][14] 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.[15] 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.[16]

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.[17]

Degradation

[edit]

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][18]

Infectious diseases

[edit]

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.[19]

Other conditions

[edit]

Foam cells may form around leaked silicone from breast implants.[20] Lipid-laden alveolar macrophages, also known as pulmonary foam cells, are seen in bronchoalveolar lavage specimens in some respiratory diseases.[21]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Foam cell

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from Grokipedia
A foam cell is a lipid-laden cell, typically derived from macrophages or vascular cells, that accumulates excessive esters and triglycerides within its , imparting a characteristic foamy appearance when viewed microscopically. These cells form primarily in the arterial intima during , where they contribute to the buildup of lipid-rich plaques by ingesting oxidized low-density lipoproteins (oxLDL) via scavenger receptors such as and SR-A. Foam cells are essential to the initiation, progression, and instability of atherosclerotic lesions, as their accumulation promotes , necrotic core expansion, and eventual plaque rupture, increasing the risk of cardiovascular events like . Foam cells originate from multiple cell types beyond macrophages, including vascular smooth muscle cells (VSMCs), which can comprise up to 40-50% of foam cells in advanced plaques, as well as endothelial cells and cells under dyslipidemic conditions. The formation process involves dysregulated : cells uptake modified through receptors without feedback inhibition, followed by esterification via acyl-CoA:cholesterol acyltransferase (ACAT) and storage in lipid droplets, while efflux pathways mediated by ATP-binding cassette transporters ( and ABCG1) become impaired. This imbalance shifts foam cells from lipid-clearing sentinels to pro-inflammatory entities that secrete cytokines, , and matrix-degrading enzymes, exacerbating plaque vulnerability. In terms of function, foam cells exhibit heterogeneity, with subtypes such as inflammatory, resident-like, and TREM2-high macrophages influencing plaque stability through processes like , , and . Their death modalities, including necroptosis and , enlarge the necrotic core and promote , underscoring their role in advanced . Emerging research highlights therapeutic potential in targeting foam cell formation, such as enhancing efflux or modulating scavenger receptor activity, though challenges remain due to their diverse origins and context-dependent behaviors.

Overview

Definition

Foam cells are lipid-laden cells, typically immune cells such as macrophages, that have accumulated excessive , primarily esters and triglycerides, within their , forming numerous lipid droplets that confer a characteristic foamy or vacuolated appearance when viewed under light microscopy. These cells derive primarily from macrophages of monocytic origin, as well as vascular cells and dendritic cells. In tissues such as arterial walls, foam cells arise from multiple cell types, including monocyte-derived macrophages that differentiate and accumulate in response to local pathological conditions. This distinguishes them from other lipid-laden cells, such as hepatocytes in non-alcoholic or adipocytes in , which serve physiological storage functions rather than arising from inflammatory immune responses. Foam cells contribute to the formation of atherosclerotic plaques by promoting retention in the vascular wall.

Significance

Foam cells play a central role in chronic by accumulating that disrupt normal immune responses and perpetuate inflammatory signaling within tissues. This lipid-laden state impairs the macrophages' ability to resolve , leading to sustained activation of pro-inflammatory pathways such as and production. Furthermore, foam cells contribute to the dysregulation of by failing to efficiently process and export excess , resulting in intracellular buildup that alters cellular metabolism and exacerbates metabolic stress. The presence of foam cells drives tissue damage across both vascular and non-vascular contexts through mechanisms including , remodeling, and induction in surrounding cells. In vascular settings, their accumulation promotes plaque and vascular wall weakening, while in non-vascular tissues, they facilitate and by releasing damaging enzymes and . Foam cells exhibit significant heterogeneity depending on the tissue microenvironment and state, manifesting as pro-inflammatory phenotypes that amplify immune responses or anti-inflammatory variants that attempt to mitigate damage. This plasticity arises from differential expression of transcription factors like STAT and PPARγ, allowing foam cells to shift between M1-like (pro-inflammatory) and M2-like () states. Such heterogeneity influences their overall impact, with pro-inflammatory foam cells exacerbating and anti-inflammatory ones potentially aiding resolution in certain contexts.

Formation

Lipid Uptake Mechanisms

Foam cells form through the excessive accumulation of in various cell types, with macrophages serving as a major source alongside vascular cells (VSMCs), endothelial cells, and others. In macrophages, this process is driven by the uptake of modified (LDL) particles, particularly oxidized LDL (oxLDL). In the arterial intima, LDL infiltrates the subendothelial space and undergoes oxidative modification due to (ROS) generated by endothelial cells and other sources. OxLDL is then recognized and internalized by macrophages via scavenger receptors, which lack the feedback regulation seen in classical LDL receptors, leading to uncontrolled lipid deposition and the characteristic foamy appearance of these cells. Key scavenger receptors mediating this uptake include , SR-A (also known as MSR1), and LOX-1. , a class B scavenger receptor, binds oxidized phospholipids on moderately to extensively oxidized LDL, facilitating rapid internalization and promoting cholesteryl ester synthesis within lipid droplets; studies in -deficient mice demonstrate a 50-60% reduction in oxLDL uptake and diminished foam cell formation. SR-A, a class A receptor, preferentially recognizes extensively oxidized LDL through lysine modifications on , accounting for 30-50% of modified LDL uptake in macrophages; genetic of SR-A in atherosclerosis-prone models reduces lesion size by over 50%, underscoring its role in lipid loading. LOX-1, primarily expressed on endothelial cells but also on macrophages, targets mildly oxidized LDL and contributes to both direct lipid uptake and endothelial activation; LOX-1 deletion in mouse models reduces atherosclerotic plaque development by approximately 40-50% by limiting oxLDL internalization. These receptors collectively enable the non-saturable accumulation of lipids, transforming resident and recruited macrophages into foam cells. Foam cells also form in VSMCs through similar mechanisms involving scavenger receptor-mediated uptake of oxLDL, often triggered by phenotypic switching from contractile to synthetic states under inflammatory conditions. VSMCs express receptors such as LOX-1, , and SR-A, leading to lipid accumulation and their contribution to up to 40-50% of foam cells in advanced plaques. This process is amplified by and local , promoting VSMC migration into the intima and exacerbating plaque progression. In addition to soluble oxLDL, macrophages contribute to foam cell formation by phagocytosing apoptotic cells and necrotic debris laden with lipids. During atherosclerosis progression, apoptotic endothelial cells, cells, and early foam cells release lipid-rich apoptotic bodies, which are engulfed via receptors such as LOX-1 and ; this process, known as , initially aids in plaque cleanup but becomes overwhelmed, leading to secondary and further lipid overload in . Impaired in advanced lesions exacerbates necrotic core expansion, as undigested debris releases more free , promoting additional foam cell generation. Hyperlipidemia and endothelial dysfunction initiate and amplify these uptake mechanisms by increasing LDL availability and promoting its modification. Elevated plasma LDL levels in hyperlipidemic states enhance subendothelial infiltration, where dysfunctional —characterized by reduced bioavailability and heightened ROS production—facilitates LDL oxidation and adhesion. This creates a pro-oxidative environment that upregulates scavenger receptor expression on infiltrating macrophages, accelerating oxLDL uptake and foam cell development.

Key Regulatory Pathways

The formation of foam cells in macrophages is tightly regulated by nuclear receptors and transcription factors that modulate uptake, metabolism, and efflux. (PPARγ) plays a central role in this process by activating genes involved in homeostasis, such as those encoding ATP-binding cassette transporters and ABCG1, which facilitate efflux and thereby inhibit excessive accumulation and foam cell development. Ligand activation of PPARγ has been shown to suppress foam cell formation through pathways independent of in some contexts, highlighting its broad regulatory influence on handling. Similarly, liver X receptor (LXR), often acting downstream of PPARγ, promotes reverse transport by upregulating and ABCG1 expression, reducing the lipid-laden state of macrophages and limiting foam cell biogenesis during atherogenesis. Agonists targeting the PPARγ/LXR axis, such as certain natural compounds, have demonstrated anti-atherosclerotic effects by enhancing this pathway and inhibiting foam cell formation in experimental models. Transcription factors like sterol regulatory element-binding proteins (SREBPs) further contribute to the regulatory landscape by controlling the expression of lipid uptake receptors. SREBP-2, in particular, induces the transcription of the receptor (LDLR), which under normal conditions maintains but can drive foam cell formation when dysregulated by inflammatory signals. Inflammatory cytokines, such as interleukin-1, interfere with SREBP processing and activity, leading to altered LDLR expression and enhanced cholesterol influx, thereby promoting a pro-foam cell phenotype in macrophages. This SREBP-mediated mechanism links to increased receptor-dependent lipid uptake, exacerbating foam cell accumulation in vascular lesions. Recent studies have identified additional regulators, including casein kinase 2-interacting protein-1 (CKIP-1), which inhibits foam cell formation by facilitating the ubiquitin- degradation of the transcription factor Oct-1 through interaction with the proteasome activator REGγ. This degradation suppresses the expression of the scavenger receptor LOX-1, reducing oxidized (oxLDL) uptake and subsequent engorgement in macrophages. Genetic deficiency of CKIP-1 in hematopoietic cells results in heightened foam cell formation and accelerated plaque development in atherosclerosis-prone mice, underscoring its protective role. The ubiquitin-specific peptidase 9X (USP9X) also serves as a key negative regulator of foam cell formation by stabilizing scavenger receptor A1 (SR-A1) through deubiquitination at lysine 27, which attenuates oxLDL binding and internalization in . USP9X expression is downregulated in atherosclerotic lesions across human and rodent models, correlating with increased macrophage lipid uptake and foam cell accumulation. Macrophage-specific disruption of USP9X enhances inflammatory responses and promotes foam cell biogenesis, further linking deubiquitination events to the control of atherogenic lipid handling.

Composition

Lipid Components

Foam cells are characterized by the accumulation of primarily in the form of esters stored within cytoplasmic lipid droplets, alongside free and phospholipids that contribute to the structural integrity of these droplets. esters represent the major neutral component, synthesized by enzymes such as acyl-CoA: acyltransferase (ACAT) to esterify excess free , preventing cellular . Free , derived from the of internalized lipoproteins, accumulates in smaller amounts but can disrupt membranes if not properly managed. Phospholipids form the shell surrounding the hydrophobic core of lipid droplets, facilitating their stability and interaction with cellular components. Triglycerides also contribute to the pool, particularly in certain foam cell subtypes, such as those derived from vascular cells. The primary sources of these in foam cells include oxidized (oxLDL) and triglyceride-rich lipoproteins like (VLDL) and remnants. This accumulation leads to the characteristic foamy appearance as engorge the cell. In advanced foam cells, lipids occupy a substantial portion of the cell volume, markedly altering cellular morphology and function. This substantial burden underscores the shift from normal physiology to a storage-dominated state, with droplets comprising the bulk of the intracellular space.

Cellular and Molecular Components

Foam cells, primarily derived from macrophages, retain key macrophage-specific markers such as even after extensive lipid loading, which underscores their monocytic origin and distinguishes them from other lipid-laden cell types in atherosclerotic lesions. This retention of expression persists in advanced foam cells within plaques, facilitating their identification through and highlighting the cellular identity preservation amid metabolic stress. Similarly, markers like Mac2 are highly expressed in these cells, reinforcing their macrophage lineage despite morphological alterations. Lipid-laden foam cells actively secrete proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), which contribute to the inflammatory milieu in atherosclerotic plaques. This secretion is upregulated in response to lipid accumulation, with studies showing increased IL-1β, IL-6, and TNF-α release from human monocyte-derived foam cells following exposure to oxidized . These cytokines amplify local and promote further recruitment of immune cells, establishing a feedback loop in plaque progression. Lipid overload in foam cells induces significant organelle remodeling, particularly in lysosomes and mitochondria, which compromises cellular . Lysosomes become enlarged and dysfunctional due to the accumulation of undigested lipids, such as esters that form the core of intracellular droplets, leading to impaired degradative capacity and lysosomal membrane permeabilization. This enlargement is observed in both models of human macrophages and atherosclerotic lesions, where late-stage foam cells exhibit bloated lysosomes filled with esterified . Concurrently, mitochondria in foam cells undergo alterations including fragmentation, reduced , and impaired , driven by lipid-induced and accumulation. These mitochondrial changes diminish ATP production and exacerbate cellular dysfunction, further perpetuating the foam cell .

Degradation

Cholesterol Efflux Processes

Cholesterol efflux represents a critical protective mechanism in foam cells, primarily macrophages laden with , enabling the removal of excess to prevent pathological accumulation. This process is essential for reverse cholesterol transport (RCT), where is transported from peripheral tissues back to the liver for excretion. In foam cells, efflux primarily occurs through active transporter-mediated pathways and passive mechanisms, maintaining cellular . The primary active efflux pathways involve ATP-binding cassette (ABC) transporters and ABCG1, which facilitate the unidirectional export of and phospholipids from the plasma . mediates efflux to lipid-poor A-I (ApoA-I), the major protein component of (HDL), generating nascent HDL particles. ABCG1 promotes efflux to mature HDL particles, enhancing the loading of esters into larger HDL subclasses. Together, and ABCG1 account for up to 70% of efflux from -loaded foam cells, with initiating HDL formation and ABCG1 supporting further lipidation, thereby amplifying overall RCT efficiency in foam cells. involves the formation of transient complexes between , ApoA-I, and , often requiring endosomal recycling for sustained activity. Passive , including aqueous efflux, provides an additional, energy-independent route for removal, contributing about 30% of total efflux in lipid-loaded macrophages. In this pathway, free desorbs from the plasma membrane into the extracellular aqueous phase down its concentration gradient, facilitated by HDL or ApoA-I as acceptors. The rate is limited by the desorption step, influenced by membrane composition, and can be enhanced by scavenger receptor BI (SR-BI), which enables selective uptake and efflux through a hydrophobic channel. Although less efficient than ABC transporter-mediated efflux, aqueous ensures basal turnover and complements active pathways in maintaining foam cell balance. Regulation of these efflux processes is tightly controlled by liver X receptors (LXRs), nuclear receptors activated by oxysterols that sense intracellular cholesterol levels. Upon activation, LXRs form heterodimers with retinoid X receptors (RXRs) and induce transcription of efflux-promoting genes, including ABCA1, ABCG1, and ApoE. LXR agonists, such as T0901317, upregulate these transporters in macrophages, significantly enhancing cholesterol efflux to ApoA-I and HDL, thereby reducing foam cell lipid content. This transcriptional control integrates cholesterol sensing with efflux capacity, underscoring LXRs' role in preventing foam cell persistence under lipid overload.

Impaired Degradation Mechanisms

Impaired degradation of lipids in foam cells primarily arises from disruptions in cholesterol efflux pathways and intracellular catabolic processes, leading to persistent lipid accumulation and cellular dysfunction. Inflammation within the atherosclerotic microenvironment suppresses the expression of key efflux transporters ABCA1 and ABCG1, thereby hindering the reverse transport of cholesterol to high-density lipoprotein (HDL) particles. Pro-inflammatory signals, such as those mediated by cytokines and Toll-like receptor activation, downregulate ABCA1 and ABCG1 transcription through inhibition of liver X receptor (LXR) signaling and induction of microRNAs that target these transporters. For instance, oxidized low-density lipoprotein (oxLDL)-induced inflammation reduces ABCA1 mRNA and protein levels in human THP-1 macrophages, impairing cholesterol efflux and exacerbating foam cell persistence. Similarly, chronic inflammatory conditions promote epigenetic modifications that silence ABCA1/ABCG1 promoters, further limiting lipid clearance in advanced lesions. Oxidative stress, a hallmark of atherogenic environments, further compromises and ABCG1 function by directly reducing their expression and activity. Exposure to (ROS) or oxLDL decreases ABCA1 gene and protein levels in macrophages via activation of stress kinases like MEK/ERK, which disrupt LXR-dependent transcriptional regulation. This oxidative modulation not only attenuates efflux to apoA-I but also amplifies intracellular , creating a vicious cycle that sustains foam cell formation. In (ER) stress contexts, often linked to oxidative damage, ABCA1 protein stability is reduced independently of mRNA changes, leading to defective cholesterol export and increased lipid droplet retention. Defective autophagy-lysosomal pathways represent another critical barrier to lipid breakdown in foam cells, as autophagy delivers lipid droplets to lysosomes for hydrolysis by acid lipase. Impairment in macroautophagy or (CMA) disrupts the fusion of with lysosomes, preventing the degradation of cholesteryl esters into free available for efflux. In advanced foam cells, accumulated inhibit autophagic flux, resulting in lysosomal dysfunction and reduced lysosomal acid lipase activity, which perpetuates intracellular storage. Studies in macrophage models demonstrate that blocking with inhibitors like 3-methyladenine increases lipid droplet size and impairs mobilization, highlighting the pathway's essential role in maintaining homeostasis. This defect is exacerbated in inflammatory settings, where ROS and cytokines further suppress autophagosome formation, leading to lysosomal overload. Genetic factors, such as LKB1 deficiency, also promote retention by altering and efflux capacity. Liver kinase B1 (LKB1), a serine/ , regulates (AMPK) signaling to enhance expression and efflux; its deficiency in macrophages, often induced by oxLDL exposure, reduces AMPK activity and impairs clearance. Research from 2017 shows that LKB1-knockout macrophages exhibit increased oxLDL uptake, resulting in heightened foam cell formation and accelerated in mouse models. Subsequent studies (2018–2022) confirm that LKB1 loss disrupts metabolic reprogramming, including reduced efflux via downregulated /ABCG1, favoring accumulation over degradation and contributing to persistent foam cell retention in plaques. These genetic influences underscore the interplay between signaling pathways and lysosomal/autophagic machinery in foam cell persistence.

Pathological Roles

Role in Atherosclerosis

Foam cells play a pivotal role in the initiation of by accumulating s within the arterial intima. Macrophages, the primary source of foam cells, infiltrate the subendothelial space and internalize oxidized (oxLDL) through scavenger receptors such as and SR-A, leading to excessive cholesterol storage in droplets and the formation of fatty streaks, which represent the earliest visible lesions of . This -laden transformation disrupts endothelial integrity and promotes recruitment, establishing a pro-atherogenic environment in the vessel wall. Vascular cells (VSMCs) also contribute to foam cell formation by undergoing phenotypic switching and uptake, further amplifying intimal deposition. In addition to initiation, foam cells drive plaque instability through the secretion of matrix metalloproteinases (MMPs) and inflammatory mediators. Activated foam cells express MMPs, including MMP-8 and MMP-9, which degrade the components of the fibrous cap, weakening plaque structure and increasing the risk of rupture. Concurrently, these cells release pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), perpetuating chronic that recruits additional immune cells and exacerbates within the plaque. Cholesterol crystals within foam cells further amplify this response by activating the , leading to heightened IL-1β production and sustained inflammatory signaling. The progression of foam cell accumulation contributes to the development of vulnerable plaques, which are prone to rupture and subsequent thrombotic events such as (MI) and . Defective — the clearance of apoptotic foam cells—results in secondary , enlarging the necrotic core and thinning the fibrous cap, hallmarks of plaque vulnerability. In advanced lesions, the coalescence of foam cell-derived lipid cores with inflammatory infiltrates destabilizes the plaque, facilitating rupture and acute coronary or cerebrovascular occlusion. This process underlies the majority of clinical manifestations of , with foam cell and directly linking chronic lipid dysregulation to life-threatening cardiovascular outcomes.

Role in Infectious Diseases

Foam cells, characterized by their lipid-laden state, play a significant role in tuberculosis (TB) by harboring Mycobacterium tuberculosis within granulomas. In TB granulomas, particularly those with necrotic cores, foam cells accumulate triglycerides derived from host debris and extracellular lipids via receptors such as CD36, creating lipid-rich environments that support bacterial persistence. These foamy macrophages differentiate in response to oxygenated mycolic acids produced by M. tuberculosis, allowing phagosomes containing the bacilli to fuse with lipid bodies, where the pathogen enters a dormant, non-replicative state and utilizes host lipids for survival. This lipid accumulation impairs the macrophages' phagocytic and bactericidal functions, contributing to chronic infection. In other infections, such as , foam cells arise from monocyte-derived macrophages exposed to HIV-derived single-stranded RNAs, which bind to 8 (TLR8) in endosomes, triggering TNFα release via MyD88 signaling and promoting uptake. This process fosters chronic inflammation by sustaining a pro-inflammatory milieu in infected tissues. Similarly, in , -laden macrophages exhibit increased neutral content and a mixed M1/M2 , secreting elevated levels of pro-inflammatory cytokines like IL-1β, IL-6, and TNFα while producing reduced reactive oxygen and species. These foam cells enhance parasite burden, particularly in under high-fat conditions, thereby perpetuating chronic inflammation and impairing T cell responses. Foam cells exhibit a dual role in infectious diseases, simultaneously providing nutrients that facilitate pathogen survival and attempting immune containment through inflammatory signaling. For instance, in TB, while lipids from foam cells nourish M. tuberculosis and promote drug tolerance, these cells also produce cytokines such as TNFα to aid formation and host defense. In and , this duality manifests as lipid provision supporting parasite or viral persistence alongside cytokine-mediated efforts to limit infection spread, though often resulting in unresolved chronic inflammation.

Role in Other Conditions

Foam cells contribute to the pathogenesis of autoimmune diseases such as by accumulating in the and promoting inflammation. In patients, exhibiting foam cell characteristics, laden with oxidized , are observed around blood vessels and deposits in the synovium, suggesting parallels to atherosclerotic processes that exacerbate joint inflammation. Experimental models of chronic antigen-induced demonstrate that hypercholesterolemia enhances foam infiltration in the synovium, leading to increased and through elevated activity. In metabolic disorders like obesity and type 2 diabetes, foam cells form within adipose tissue macrophages, contributing to insulin resistance and chronic inflammation. Visceral adipose tissue in obese individuals shows increased lipid-laden foam cells derived from macrophages, which correlate with higher cardiometabolic risk and adipose dysfunction, as evidenced by associations between circulating non-classical monocytes and macrophage lipid content (r=0.303, p<0.05). In type 2 diabetes models, pro-inflammatory M1 macrophages accumulate modified low-density lipoprotein, forming foam cells that impair lipid homeostasis; however, interleukin-4 polarization to M2 macrophages upregulates cholesterol efflux transporters like ABCA1 and ABCG1, reducing foam cell formation and mitigating metabolic stress. Emerging evidence highlights the role of foam cells in cancer progression through tumor-associated macrophages that adopt lipid-laden phenotypes. In , cancer-associated foam cells accumulate at tumor margins, suppressing + T cell immunity via TGF-β secretion while increasing regulatory T cells, resulting in poorer prognosis in low tumors (3-year disease-free survival: 8.6% in high-foam cell vs. 28.7% in low-foam cell tumors, p=0.001), particularly in patients with high BMI. Similarly, in , protumoral lipid droplet-loaded macrophages (tumor-associated foam cells) are enriched, promoting hypoxia, , and mesenchymal transition while impairing , with their formation driven by lipid scavenging from tumor-derived extracellular vesicles; targeting lipid synthesis enzymes like diacylglycerol O-acyltransferase disrupts this process and improves outcomes. Foam cells also appear in other non-infectious conditions, such as -induced granulomas and respiratory diseases. In injection-related granulomas, histiocytes and multinucleated giant cells exhibit foamy due to phagocytosed droplets, leading to chronic granulomatous in affected tissues like the pleura or skin. In respiratory pathologies like and , alveolar transform into foam cells following exposure to silica or , where uptake from injured pneumocytes induces an M2 and TGF-β1 production, driving fibrotic remodeling; excess iron further promotes foamy macrophage emergence with overexpression in lungs, independent of .

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