Published online before print October 7, 2008

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(Journal of Leukocyte Biology. 2009;85:186-193.)
© 2009 by Society for Leukocyte Biology

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

B. M. Maher^*,1, T. Ni Dhonnchu, J. P. Burke^*, A. Soo^*,, A. E. Wood and R. W. G. Watson^*

^* UCD School of Medicine and Medical Sciences, UCD Conway Institute, University College Dublin, Dublin, Ireland; and
Professor Eoin O’Malley National Centre for Cardiothoracic Surgery, Mater Misericordiae University Hospital, Dublin, Ireland

¹ Correspondence: UCD School of Medicine and Medical Sciences, UCD Conway Institute and Mater Misericordiae University Hospital, University College Dublin, Dublin, Ireland. E-mail: belinda.maher{at}ucd.ie

ABSTRACT

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.

Key Words: ischemic reperfusion injury • atherosclerosis • arthritis • Crohn’s disease • reductase

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