Neutrophils promote early atherosclerosis
MedWire News: Researchers have found that neutrophils have an important role in the initiation of atherosclerosis, opening up the possibility of new targets for preventive therapies.
Oliver Soehnlein (RWTH Aachen University, Germany) and colleagues show that hypercholesterolemia in mice results in neutrophilia, and that this correlates with the extent of early atherosclerosis formation.
The researchers fed mice lacking the apolipoprotein E gene (Apoe-/- mice) a high-fat diet (HFD), and compared peripheral neutrophil counts and neutrophil recruitment to atherosclerotic lesions with each of these measures in Apoe-/- mice fed a normal diet. They also measured the association of neutrophil count with lesion formation.
Soehnlein's team found that there was a 90% positive correlation between the number of circulating neutrophils and the extent of early atherosclerosis formation in Apoe-/- mice fed a HFD.
These mice had increased neutrophil counts compared with those fed a normal diet (6.5 vs 4.25 x105/ml after 4 weeks), due to enhanced granulopoiesis and bone marrow mobilization, and reduced peripheral clearance.
Neutrophils in HFD-mice predominantly infiltrated large arteries during the early stages of atherosclerosis, with levels peaking at 4 weeks (2.14 x103/aorta) and decreasing thereafter (1.71 and 1.0 x103/aorta at 8 and 16 weeks, respectively).
The recruitment of neutrophils to large arteries depended on the C-C chemokine receptors (CCR)1, CCR2, and CCR5, and the CXC receptor (CXCR)2, a finding that contrasts with peripheral venous recruitment, which requires only CCR2 and CXCR2.
Writing in the journal Circulation, the team suggests that CCR1 and CCR5 play important roles in atherogenesis, supported by the finding that CCR1 and CCR5 involvement in HFD-mice corresponded with deposition of the platelet-derived chemokine ligand (CCL)5 in arteries, but not in veins.
They also cite previous research showing that neutropenic mice have reduced plaque sizes at early but not late stages of atherosclerotic lesion formation, evidence that once neutrophils have emigrated to the arteries they promote plaque formation.
In an accompanying editorial, Stanley Hazen from the Lerner Research Institute in Cleveland, Ohio, USA, said that the study provides "convincing data to support a role for hypercholesterolemia-induced neutrophilia as a critical enabling process in early stages of atherosclerosis."
He added that although the underlying mechanisms through which early atherosclerotic changes are promoted are still unclear, the findings point towards new potential avenues for therapeutic targeting.
MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010
By Nikki Withers