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Interview with: Dr. Klingenberg, Dr. Gerdes
Q: Dr. Klingenberg, Dr. Gerdes, congratulations to your recent publication in the Journal of Clinical Investigation. Can you summarize the rationale of this study and your main findings?A: Earlier studies indirectly suggested that regulatory T cells (Tregs) ameliorate atherosclerosis, but exactly how they operate remained unclear. Using a genetically modified mouse model for selective depletion of these anti-inflammatory cells we aimed to determine the causality and the mechanism of action of Treg in atherogenesis. Indeed, depletion of Tregs led to doubling of atherosclerotic lesion size and a profound increase in circulating cholesterol concentration, mainly in the very low density lipoprotein (VLDL) fraction. We could further demonstrate that expression of a receptor important in the uptake of cholesterol-rich lipoproteins, sortilin-1, was decreased in the liver and is likely responsible for decreased clearance of pro-atherogenic particles leading to elevated blood cholesterol levels and enhanced atherosclerosis.
Q: Please briefly explain the mouse model you used in your study.A: To define the role of Foxp3-expressing Tregs in atherosclerosis, we used the DEpletion of REGulatory T cells (DEREG) mouse, which expresses the human diphtheria toxin (DT) receptor and enhanced green fluorescent protein (eGFP) under control of the Treg-specific Foxp3 promoter, allowing for specific depletion and tracking of Foxp3+ Tregs. Lethally irradiated, atherosclerosis-prone, LDLR–deficient (Ldlr–/–) mice received DEREG or wild type bone marrow and were injected with DT or PBS as control, respectively. Thus, four groups of mice were generated allowing for selective study of DT-mediated depletion of Foxp3+ Tregs on atherogenesis. Simultaneous to DT-treatment, lesion formation in the aortic root was induced by feeding an atherogenic diet for 8 weeks and atherosclerotic burden was compared to control-treated mice receiving PBS with functional Tregs.
Q: Unexpectedly, elimination of FoxP3-expressing Tregs did not increase vascular inflammation, but the major effect was a modulation of lipoprotein metabolism. How did you proceed to clarify the underlying processes in order to explain this observation? And what did you find?A: Indeed, the atherosclerotic lesions of the DT-treated mice displayed characteristics of very advanced plaques full of lipids but containing few cells. After discovering the profound increase in VLDL cholesterol in DT-treated mice we performed assays for lipoprotein synthesis and clearance and could pinpoint the defect to an impaired uptake of cholesterol-rich VLDL particles in the liver. We established several close collaborations with experts of lipidology throughout Scandinavia. A dual strategy proved fruitful: functional assessment of candidate proteins/enzymes and a gene array on the two major organs involved in lipid metabolism, liver and intestine. Convincingly, both approaches helped identify four candidates which are modulated by Treg depletion: increased expression and activity of hepatic lipase, lipoprotein lipase, and phospholipid transfer protein as critical regulators of lipoprotein composition and turnover and decreased hepatic expression of sortilin-1, a receptor recently identified as a major mediator for uptake of cholesterol-rich lipoproteins in the absence of the LDL receptor. Impairment of sortilin-1 in a system lacking the LDL receptor leads to accumulation of VLDL particles in the circulation while enhanced plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein cause an increased cholesterol/triglyceride ratio of the VLDL particles.
Q: What are the next steps for the future?A: Our study provides new insight into how Tregs interact with and impact on lipid metabolism. Future work will address three major aspects: First, how exactly do Tregs control expression of sortilin-1in the liver and is the observed impairment of VLDL clearance still operative when the main receptor for uptake of cholesterol, the LDL receptor, is functional? Second, how can therapeutic modulation of Treg-function be used to alter pro-atherogenic hypercholesterolemia and vice versa. Third, to what extent does the anti-inflammatory function of Foxp3+Treg control atherogenesis as opposed to their lipid-altering functions?
Q: Dr. Klingenberg, Dr. Gerdes, thank you for your time to discuss these exciting findings with us.
Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosisJ Clin Invest. 2013;123(3):1323–1334