What is the clinical evidence from this study?

Population: Atherosclerosis. Intervention: Hemoglobin. Primary outcome: Macrophage differentiation.

What question did this study set out to answer?

To examine the stimuli and mechanisms controlling macrophage differentiation in regions of intraplaque hemorrhage within human atherosclerotic lesions.

August 26, 2026Journal of the American College of Cardiology

Hemoglobin Directs Macrophage Differentiation and Prevents Foam Cell Formation in Human Atherosclerotic Plaques

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Key result

Plaque hemoglobin exposure drives macrophage differentiation into a non-foam phenotype by lowering iron and ROS.

Why the study?

Does hemoglobin exposure direct macrophage differentiation and prevent foam cell formation in atherosclerotic plaques?

Key Points

To examine the stimuli and mechanisms controlling macrophage differentiation in regions of intraplaque hemorrhage within human atherosclerotic lesions.
Evaluated macrophage phenotypes within human atherosclerotic plaques and an in vivo rabbit hemorrhage sponge model exposed to red blood cells.
Cultured primary human monocytes with hemoglobin:haptoglobin complexes and measured lipid accumulation, iron transport, and reactive oxygen species levels.
Tested the regulatory role of liver X receptor alpha (LXRα) and ferroportin on ABC transporter expression and cholesterol efflux using hepcidin treatment and gene knockdown.
Hemoglobin-stimulated macrophages marked by high CD163 and mannose receptor expression localized to intraplaque hemorrhage sites and resisted lipid accumulation characteristic of foam cells.
Hemoglobin exposure induced ferroportin expression, depleting intracellular iron and suppressing reactive oxygen species, which subsequently activated LXRα and upregulated ABC transporters.
Hepcidin-mediated degradation of ferroportin increased reactive oxygen species, suppressed ABCA1, and impaired cholesterol efflux to ApoAI, confirming that iron-dependent oxidative stress regulates reverse cholesterol transport.

Structured PICO

Does hemoglobin exposure direct macrophage differentiation and prevent foam cell formation in atherosclerotic plaques?

Population

Freshly isolated human monocytes, a rabbit model of hemorrhage, and human atherosclerotic plaques

Exposure

Exposure to hemoglobin (Hb) or hemoglobin:haptoglobin complexes (Hb:Hp)

Comparator

IL-4 (for cultured human monocytes) or control conditions without red cell exposure (in rabbit model)

Outcome

Macrophage differentiation phenotype, lipid accumulation, ABC transporter expression, and reactive oxygen species (ROS) levelssurrogate

Implication

Hemoglobin directs macrophage differentiation into a non-foam cell phenotype characterized by reduced intracellular iron, decreased ROS, and increased reverse cholesterol transport via LXRα activation.

Abstract

Objectives To examine selective macrophage differentiation occurring in areas of intraplaque hemorrhage in human atherosclerosis. Background Macrophage subsets are recognized in atherosclerosis but the stimulus for and importance of differentiation programs remains unknown. Methods We used freshly isolated human monocytes, a rabbit model, and human atherosclerotic plaques to analyze macrophage differentiation in response to hemorrhage. Results Macrophages characterized by high expression of both mannose and CD163 receptors preferentially exist in atherosclerotic lesions at sites of intraplaque hemorrhage. These hemoglobin (Hb)-stimulated macrophages, M(Hb), are devoid of neutral lipids typical of foam cells. In vivo modeling of hemorrhage in the rabbit model demonstrated that sponges exposed to red cells showed an increase in mannose receptor positive macrophages only when these cells contained hemoglobin (Hb). Cultured human monocytes exposed to hemoglobin:haptoglobin complexes (Hb:Hp), but not IL-4, expressed the M(Hb) phenotype and were characterized by their resistance to cholesterol loading and upregulation of ABC transporters. M(Hb) demonstrated increased ferroportin (FPN) expression, reduced intracellular iron, and reactive oxygen species (ROS). Degradation of FPN using hepcidin increased ROS, inhibited ABCA1 expression, and cholesterol efflux to ApoAI, suggesting reduced ROS triggers these effects. Knockdown of liver x receptor alpha (LXRα) inhibited ABC transporter expression in M(Hb) and macrophages differentiated in the anti-oxidant superoxide dismutase. Lastly, liver X receptor α (LXR) luciferase reporter activity was increased in M(Hb) and significantly reduced by overnight treatment with hepcidin. Collectively, these data suggest reduced ROS triggers LXRα activation and macrophage reverse cholesterol transport (RCT). Conclusions Hb is a stimulus for macrophage differentiation in human atherosclerotic plaques. A reduction of macrophage intracellular iron plays an important role in this non- foam cell phenotype by reducing ROS, which drives transcription of ABC transporters through activation of LXRα. Reduction of macrophage intracellular iron may be a promising avenue to increase macrophage RCT.

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Cite This Study

Finn et al. (2011) studied Atherosclerosis. Hemoglobin was evaluated on Macrophage differentiation. Hemoglobin exposure in atherosclerotic plaques stimulates macrophage differentiation into a non-foam cell phenotype by reducing intracellular iron and reactive oxygen species.

synapsesocial.com/papers/6a8eaf77c654ed1bd5587d11 https://doi.org/10.1016/j.jacc.2011.10.852

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