Monocytes and neutrophils : accomplices in initiation and development of atherosclerosis

Atherosclerosis is currently viewed as a chronic inflammatory disease of the arterial vessel wall with prominent roles for endothelial cells, T lymphocytes and monocyte-derived cells. Hypercholesterolemia is a major risk factor activating these cell types resulting in enhanced expression of cell adhesion molecules, chemokines, and pro-inflammatory cytokines ultimately promoting arterial infiltration with immune cells. Monocytes/macrophages are traditionally seen as main actors in development and progression of atherosclerosis. However, relevance of the two principal monocyte subsets has so far not taken into account. Although a recent study deals with expansion of inflammatory monocytes under hyperlipidemia96 detailed mechanisms as well as the importance of either monocyte subset itself still remains elusive. Neutrophils are a so far underappreciated leukocyte subset in atherosclerosis. Recent work suggests a prominent role for these cells and this study is the first to link early stages of atherosclerosis to hypercholesterolemia-induced neutrophilia which can be attributed to stimulation of granulopoiesis, enhanced bone marrow mobilization as well as reduced peripheral clearance. Increased peripheral neutrophil counts were found to closely correlate with the extent of early atherosclerosis formation. In these initial stages, neutrophils prominently infiltrate arteries through the involvement of CCR1, CCR2, CCR5, and CXCR2. The utilization of CCR1 and CCR5 contrasts to peripheral neutrophil recruitment and may be ascribed to endothelial deposition of CCL5 by platelets. Once emigrated, neutrophils promote atherogenesis as evidenced by reduced plaque sizes in neutropenic mice. Thus, the employment of CCR1 and CCR5 in arterial but not venous recruitment may emerge as a feasible option for therapeutic targeting. Clearly, the addition of the neutrophil as a previously not fully appreciated player in atherosclerosis increases the complexity of cellular interactions in disease pathogenesis, but also harbours valuable strategies for prevention and treatment. In the second part of this work the importance of either monocyte subset was dissected. Besides increases in M-CSF-driven production of Gr1+ monocytes a new link between augmented CXCL1 levels and CXCR2 expressed by inflammatory monocytes provide insights to mechanisms underlying HFD-induced monocytosis. Inflammatory monocytes were clearly shown to be key players in atheroprogression rather than Gr1- monocytes. Contrasting previous studies only CCR1 and CCR5 were crucial for Gr1+ moncytes to enter atherosclerotic arteries. However, neither CCR2 nor CX3CR1 were essential in monocyte recruitment as deficiency of those receptors did not uncouple the tight correlation between peripheral Gr1+ monocyte counts and arterial monocyte numbers. These results were further corroborated by an adoptive transfer experiment implying a more essential role of CCR2 and CX3CR1 in monocyte homeostasis and life cycle. In conclusion, the here presented work illustrates a partnership of neutrophils and monocytes in onset and development of atherosclerosis which can be characterized to be an ill-alliance. However, underlying mechanism concerning neutrophil-induced monocyte recruitment remains elusive and future studies shedding light on these interactions are needed.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2011

Author dc:creator

• Drechsler, Maik

Contributors dc:contributor

• Weber, Christian

• info:eu-repo/classification/ddc/570
• Monozyt
• Neutrophiler Granulozyt
• Arteriosklerose
• Pathogenese
• Chemokine
• Biowissenschaften, Biologie
• monocyte
• neutrophil
• atherosclerosis
• pathogenesis

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124421%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62948