Statins alter neutrophil migration by modulating cellular Rho activity—a potential mechanism for statins-mediated pleotropic effects?

The ability of neutrophils to sense and migrate toward damaged tissue is a vital component of the innate immune response. Paradoxically, this same migration serves as the hallmark of a number of inflammatory conditions, including ischemic reperfusion injury, atherosclerosis, arthritis, and Crohn...

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Bibliographic Details
Published in:Journal of leukocyte biology 2009-01, Vol.85 (1), p.186-193
Main Authors: Maher, B. M., Dhonnchu, T. Ni, Burke, J. P., Soo, A., Wood, A. E., Watson, R. W. G.
Format: Article
Language:English
Subjects:
arthritis
atherosclerosis
Atorvastatin Calcium
Cells, Cultured
Chemotactic Factors - pharmacology
Crohn's disease
Endothelial Cells - cytology
Endothelial Cells - metabolism
Endothelium, Vascular - cytology
Heptanoic Acids - pharmacology
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
ischemic reperfusion injury
N-Formylmethionine Leucyl-Phenylalanine - pharmacology
Neutrophil Infiltration - drug effects
Neutrophil Infiltration - physiology
Neutrophils - drug effects
Neutrophils - physiology
Polyisoprenyl Phosphates - metabolism
Pravastatin - pharmacology
Pyrroles - pharmacology
reductase
rhoA GTP-Binding Protein - physiology
Simvastatin - pharmacology
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Summary:The ability of neutrophils to sense and migrate toward damaged tissue is a vital component of the innate immune response. Paradoxically, this same migration serves as the hallmark of a number of inflammatory conditions, including ischemic reperfusion injury, atherosclerosis, arthritis, and Crohn's disease. More recent evidence suggests that neutrophil infiltration into the cardiac allograft following transplantation is a contributing factor in allograft rejection. We have demonstrated previously a positive correlation between the degree of neutrophil migration and subsequent rejection grades in a cohort of cardiac transplant recipients. Intracellular signaling pathways that are intimately involved in neutrophil migration thus offer potential targets of manipulation in the treatment of such conditions. 3‐Hydroxy‐3‐methylyglutaryl‐coenzyme A reductase inhibitors or statins are emerging as potential anti‐inflammatory agents and have a proven survival benefit in the transplant population. Yet, little is known about their ability to modulate neutrophil function and their subsequent mechanism of action. We demonstrate here that pravastatin, simvastatin, and atorvastatin significantly reduce neutrophil transendothelial migration toward the chemoattractant fMLP. This effect is independent of any change in neutrophil adhesion or adhesion molecule expression but is related to the ability of statins to reduce fMLP‐induced Rho activity in neutrophils. This was confirmed by the ability of the Rho precursor geranylgeranyl pyrophosphate to rescue the statin‐mediated reduction in neutrophil transendothelial migration. Understanding the mechanisms of action of statins in the neutrophil allows for their use in targeting excessive migration in inappropriate inflammatory conditions.
ISSN:0741-5400
1938-3673
DOI:10.1189/jlb.0608382