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Published on: April 3, 2017
CXCL4-induced macrophages in human atherosclerosis
Gabriele Domschke1, Christian A Gleissner1
1Dept. of Cardiology, Angiology and Pneumonology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Insights
Platelet factor-4 (PF4) drives monocyte differentiation into M4 macrophages, a pro-inflammatory cell type found in unstable atherosclerotic plaques. These M4 macrophages may offer new diagnostic and therapeutic targets for atherosclerosis.
Area of Science:
- Cardiovascular Biology
- Immunology
- Inflammation Research
Background:
- Atherosclerosis is an inflammatory arterial disease where monocytes and platelets are key players.
- Monocytes differentiate into macrophages, internalize lipids, form foam cells, and release pro-inflammatory cytokines.
- Platelets secrete chemokines that mediate inflammatory and immune responses in atherogenesis.
Purpose of the Study:
- To review the role of platelet factor-4 (PF4) in monocyte and macrophage biology within atherosclerosis.
- To elucidate the formation and characteristics of PF4-induced M4 macrophages.
- To explore the diagnostic and therapeutic potential of M4 macrophages in atherosclerotic disease.
Main Methods:
- Review of existing literature on PF4, monocytes, macrophages, and atherosclerosis.
- Analysis of PF4's interaction with monocytes and endothelial cells.
- Identification and characterization of a novel macrophage phenotype (M4) induced by PF4.
- Validation of M4 macrophage markers (CD68, S100A8, MMP7) in vitro and in vivo.
Main Results:
- PF4, in conjunction with CCL5, promotes monocyte adhesion to endothelial cells and subsequent diapedesis.
- PF4 induces a unique macrophage phenotype, termed "M4," characterized by the loss of CD163.
- M4 macrophages are identifiable by CD68, S100A8, and MMP7 and are found in atherosclerotic lesions.
- M4 macrophages are prevalent in the intima and adventitia of human atherosclerotic plaques and associated with plaque instability.
Conclusions:
- PF4-induced M4 macrophages represent a distinct pro-inflammatory cell population in atherosclerosis.
- The presence and characteristics of M4 macrophages correlate with plaque instability.
- M4 macrophages present a promising target for future diagnostic and therapeutic strategies in managing atherosclerotic disease.
Abstract:
Atherosclerosis is considered an inflammatory disease of the arterial wall. Monocytes and monocyte-derived cells (most often termed macrophages) play an essential role in the formation of atherosclerotic lesions, as they take up lipids leading to subsequent foam cell formation accompanied by release of pro-inflammatory cytokines. Similarly, platelets have been discovered to represent an important cell type mediating inflammatory and immune processes in atherogenesis, mainly by secreting chemokines, which are stored in the platelets' alpha granules, upon platelet activation. Therefore, the interaction between monocyte-derived cells and platelets is of exceptional importance. In this review, we specifically focus on the chemokine (platelet factor-4, PF4) and its effects on monocytes and monocyte-derived cells. By formation of heterodimers dimers and -oligomers with CCL5, CXCL4 induces binding of monocytes cells to endothelial cell and thereby promotes diapedesis of monocytes into the subendothelial space. CXCL4 also affects the differentiation of monocytes as it induces a specific macrophage phenotype, which we suggested to term "M4". For example, CXCL4-induced macrophages irreversibly lose the hemoglobin-haptoglobin scavenger receptor CD163. The combination of CD68, S100A8, and MMP7 turned out to reliably identify M4 macrophages both in vitro and in vivo within atherosclerotic lesions. In human atherosclerotic plaques, M4 macrophages are predominantly present in the adventitia and the intima and their prevalence is associated with plaque instability suggesting that they are a marker of pro-inflammatory activity. Overall, CXCL4-induced M4 macrophages may represent a target for diagnostic and therapeutic interventions in human atherosclerotic disease.
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