Cited by 93Protein Kinase Regulation and GTPase SignalingNeutrophil, Myeloperoxidase and Oxidative MechanismsCell Adhesion Molecules Research

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

Maher, B M, Dhonnchu, T Ni, Burke, J P, Soo, A, Wood, A E, Watson, R W G·2009·Journal of Leukocyte Biology

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.

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Crossref · 10.1189/jlb.0608382

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Authors
Maher, B. M., Dhonnchu, T. N., Burke, J. P., Soo, A., Wood, A. E., & Watson, R. W. G.
Affiliations
  • University College Dublin (IE)
  • Mater Misericordiae University Hospital (IE)
Corresponding author
Maher, B M
Venue
Journal of Leukocyte Biology
Published
2008-10-07
Volume
85
Issue
1
Pages
186-193
ISSN
  • 0741-5400 (ISSN-L)
  • 1938-3673
OpenAlex
W2061917180
Cited by
93
References
40
Citations by year
2026: 2 · 2025: 2 · 2024: 3 · 2022: 5 · 2021: 3 · 2020: 3 · 2019: 5 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 8 · 2014: 8 · 2013: 6 · 2012: 12
FWCI
3.01
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Leukocyte Biology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
Keywords
statins, neutrophil migration, transendothelial migration, fMLP, geranylgeranyl pyrophosphate, pravastatin, simvastatin, atorvastatin, cardiac allograft rejection, inflammation, innate immunity
MeSH terms
Atorvastatin, Cells, Cultured, Chemotactic Factors, Endothelium, Vascular, Heptanoic Acids, Humans, N-Formylmethionine Leucyl-Phenylalanine, Neutrophils, Polyisoprenyl Phosphates, Pyrroles, Pravastatin, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Simvastatin, Neutrophil Infiltration, rhoA GTP-Binding Protein, Endothelial Cells

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