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An Efficient and High Yield Method for Isolation of Mouse Dendritic Cell Subsets
Published on: April 18, 2016
Dual mode of HMG-CoA reductase inhibition on dendritic cell invasion
Sieglinde Kofler1, Christoph Schlichting, Sarika Jankl
1Medizinische Klinik und Poliklinik I, University Medical Center Munich-Grosshadern, Ludwig-Maximilians University of Munich, Munich, Germany.
Insights
Statins reduce dendritic cell (DC) invasion, a key factor in atherosclerosis. This effect involves the mevalonate pathway, impacting DC adhesion and transmigration, potentially offering new therapeutic avenues for inflammatory diseases.
Area of Science:
- Immunology
- Cardiovascular Biology
- Pharmacology
Background:
- Atherosclerosis is a chronic inflammatory disease driven by lipid disturbances and endothelial injury.
- Dendritic cells (DCs) are crucial immune cells that initiate inflammatory responses and play a role in atherogenesis.
- Statins are widely used for lipid-lowering but may possess immunomodulatory effects relevant to atherosclerosis.
Purpose of the Study:
- To investigate the impact of statins on dendritic cell (DC) invasion.
- To elucidate the role of the mevalonate pathway in statin-mediated effects on DCs.
- To explore the mechanisms underlying statin-induced modulation of DC-endothelial cell interactions.
Main Methods:
- Dendritic cells were incubated with atorvastatin (ATV) at varying concentrations.
- DC adhesion and transmigration assays were performed.
- The effects of mevalonate pathway intermediates, cholesterol, and specific enzyme inhibitors (wortmannin, ADMA, geranylgeranyltransferase, farnesyltransferase) were assessed.
- The involvement of the Akt/NOS pathway was examined.
Main Results:
- Low to moderate atorvastatin concentrations (0.05-0.5 microM) decreased DC invasion, reversible by mevalonate and cholesterol.
- High-dose statins (1 microM) also decreased DC invasion, reversible by geranyl pyrophosphate and cholesterol.
- Inhibition of geranylgeranyltransferase, but not farnesyltransferase, significantly reduced DC invasion.
- Statin effects at low-moderate doses were linked to altered DC cholesterol synthesis and Akt/NOS pathway activation.
- At high doses, statins reduced DC invasion via inhibition of protein geranylgeranylation.
Conclusions:
- Statins, through modulation of the mevalonate pathway, significantly inhibit dendritic cell invasion.
- Mechanisms involve altered cholesterol synthesis, Akt/NOS pathway activation, and geranylgeranylation inhibition.
- Regulating DC-endothelial cell interactions by statins may be a key mechanism in their anti-atherogenic and anti-inflammatory effects.
Abstract:
Atherosclerosis is a chronic disease triggered by lipid disturbances, endothelial injury and sustained by inflammation. Dendritic cells (DCs) are critical for the cell-mediated arm of an immune response and are known to initiate inflammatory immunity. We investigated the role of statins and the mevalonate pathway on DC invasion. DC incubation with atorvastatin (ATV; 0.05-1 microM) for 24h decreased DC adhesion capacity. DC invasion (adhesion/transmigration) was decreased after exposing DCs to low and moderate concentrations of statins, which was reversible by mevalonate (but not geranyl- or farnesyl-pyrophosphate) and cholesterol. Inhibition of the phosphoinositide 3-kinase (with wortmannin) and inhibition of the NO-synthase (with asymmetric dimethyl ADMA) partially reversed statin-mediated effects. High-dose statins markedly decreased DC invasion, which was reversible by adding geranyl pyrophosphate and cholesterol. Inhibition of geranylgeranyltransferase but not inhibition of farnesyltransferase significantly decreased DC invasion. Statin-mediated alteration in DC-cholesterol synthesis and subsequent activation of the Akt/NOS pathway accounts for the statin-induced decrease in DC invasion at low-moderate concentrations (0.05-0.5 microM). Additionally, at high statin concentrations (1 microM) DC invasion is reduced by inhibition of protein geranylgeranylation. As DCs control immunity, regulating DC/endothelial cell interaction by statins may have relevance to inflammation and atherogenesis.
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