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Published on: June 30, 2016
TGF-beta reduced binding of high-density lipoproteins in murine macrophages and macrophage-derived foam cells
S H Zuckerman1, C Panousis, G Evans
1Division of Cardiovascular Research, Lilly Research Laboratories, Indianapolis, IN 46285, USA. zuckerman_steven@lilly.com
Insights
Transforming growth factor-beta (TGF-beta) reduces high-density lipoprotein (HDL) binding to macrophages and foam cells by decreasing scavenger receptor expression. This suggests TGF-beta influences atherosclerosis progression by modulating HDL-foam cell interactions.
Area of Science:
- Immunology
- Cardiovascular Biology
- Molecular Biology
Background:
- Macrophage scavenger receptors, like CD36, bind ligands including high-density lipoprotein (HDL).
- Transforming growth factor-beta (TGF-beta) influences macrophage functions and is found in atherosclerotic lesions.
- Intracellular cholesterol and cytokines regulate scavenger receptor expression and macrophage activity.
Purpose of the Study:
- To investigate the effect of TGF-beta on HDL binding by macrophages and macrophage-derived foam cells.
- To determine if TGF-beta modulates the expression of scavenger receptors involved in HDL binding.
Main Methods:
- Macrophages and foam cells from various mouse models were used.
- Fluorescently labeled HDL was used to quantify HDL binding.
- Messenger RNA (mRNA) levels for CD36 and SR-BI were measured using quantitative real-time PCR.
- Dexamethasone was used as a comparative agent.
Main Results:
- TGF-beta significantly reduced HDL binding to macrophages and foam cells in a dose-dependent manner.
- This reduction in HDL binding correlated with decreased CD36 mRNA levels.
- TGF-beta also downregulated SR-BI mRNA, though to a lesser extent.
- Dexamethasone mimicked the effects of TGF-beta on HDL binding and CD36 mRNA levels.
Conclusions:
- TGF-beta modulates HDL binding to macrophages and foam cells, potentially impacting atherosclerosis.
- The observed effects are mediated through the downregulation of scavenger receptor expression, particularly CD36.
- Agents that inhibit macrophage inflammatory responses, like TGF-beta, may influence lesion progression by altering HDL-foam cell interactions.
Abstract:
The expression of macrophage scavenger receptors is regulated by intracellular cholesterol levels, as well as by cytokines affecting macrophage effector functions. CD36, a member of the type B scavenger receptor family, will bind a variety of nonlipoprotein and lipoprotein ligands including high-density lipoprotein (HDL). Transforming growth factor-beta (TGF-beta) has been demonstrated to modulate macrophage effector functions and is present within atherosclerotic lesions. In the present study, the effect of TGF-beta on HDL binding by both macrophages and macrophage-derived foam cells was evaluated. TGF-beta, in a dose-dependent manner, reduced the binding of flurochrome-labeled HDL to both macrophages and foam cells. These effects were observed in macrophages derived from nonatherosclerotic (BALB/c) as well as from macrophages obtained from both apolipoprotein E and low-density lipoprotein receptor knockout mice. The decrease in HDL binding was consistent with a significant reduction in CD36 message levels. The effect of TGF-beta on type B scavenger receptor expression was not limited to CD36 as SR-BI message was also downregulated, although the effect was more modest. A similar reduction in HDL binding and CD36 message was also observed with the immunosuppressive glucocorticoid dexamethasone. These results suggest that within the microenvironment of an atherosclerotic lesion, TGF-beta and other agents that inhibit macrophage inflammatory responses may impact lesion progression through mechanisms that include the modulation of HDL-foam cell interactions.
