Statins alter neutrophil migration by modulating cellular Rho activity–a potential mechanism for statins-mediated pleotropic effects?
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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Pravastatin, simvastatin, and atorvastatin reduce neutrophil transendothelial migration.
“Pravastatin, simvastatin, and atorvastatin were shown to reduce neutrophil transendothelial migration (Maher et al., 2009)”
From Atorvastatin Reduces the Survival of Candida albicans-Infected BALB/c Mice (2015) · cites this paper as Maher et al., 2009
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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
- Publisher
- Oxford University Press (OUP)
- 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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