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Updated: May 5, 2026
Culture of Macrophage Colony-stimulating Factor Differentiated Human Monocyte-derived Macrophages
Published on: June 30, 2016
Intermedin inhibits macrophage foam-cell formation via tristetraprolin-mediated decay of CD36 mRNA
Xiao-Yan Dai1, Yan Cai, Weiliang Sun
1Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, P. R. China.
Aims:
CD36-mediated uptake of oxidized low-density lipoprotein (oxLDL) plays a pivotal role in macrophage foam-cell formation and atherogenesis. Previously we reported on intermedin (IMD), a novel member of the calcitonin gene-related peptide family, in atherosclerotic plaque reducing atherogenesis in apolipoprotein E-deficient (apoE(-/-)) mice. Here, we studied the role of IMD in CD36-mediated macrophage foam-cell formation.
Methods And Results:
In apoE(-/-) mice, 6-week IMD infusion reduced oxLDL uptake, intracellular cholesterol content, and foam-cell formation in peritoneal macrophages and reduced protein and mRNA levels of CD36. These in vivo results agreed with in vitro observations in primary peritoneal macrophages. Reduced CD36 protein and mRNA levels were due to an IMD-accelerated decay of CD36 mRNA. Tristetraprolin (TTP), which binds to AU-rich elements in the 3' untranslated regions (UTRs) of mRNA and promotes its degradation, mediated CD36 mRNA destabilization. TTP knockdown by short-hairpin RNA increased and TTP overexpression reduced CD36 expression, and TTP knockdown rescued IMD-reduced CD36 expression. Moreover, IMD repressed TTP phosphorylation, thereby activating TTP, for increased TTP binding to the 3'-UTR of CD36 mRNA.
Conclusion:
Thus, IMD attenuates macrophage foam-cell formation via TTP-mediated degradation of CD36 mRNA. Our findings reveal a new mechanism of the anti-atherogenic role of IMD and a novel pattern for regulation of CD36 expression in macrophages.
Insights
Intermedin (IMD) reduces macrophage foam-cell formation by accelerating CD36 mRNA decay through activating Tristetraprolin (TTP). This reveals a new mechanism for IMD
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Immunology
Background:
- CD36-mediated uptake of oxidized low-density lipoprotein (oxLDL) is crucial for macrophage foam-cell formation and atherosclerosis.
- Intermedin (IMD), a calcitonin gene-related peptide family member, has previously shown anti-atherogenic effects in apolipoprotein E-deficient (apoE(-/-)) mice.
Purpose of the Study:
- To investigate the role of IMD in CD36-mediated macrophage foam-cell formation.
Main Methods:
- In vivo studies using IMD infusion in apoE(-/-) mice.
- In vitro studies using primary peritoneal macrophages.
- Analysis of CD36 mRNA and protein levels, and Tristetraprolin (TTP) activity.
- Short-hairpin RNA (shRNA) knockdown and overexpression of TTP.
Main Results:
- IMD infusion reduced oxLDL uptake, intracellular cholesterol, and foam-cell formation in macrophages from apoE(-/-) mice.
- IMD decreased CD36 protein and mRNA levels by accelerating CD36 mRNA decay.
- This effect was mediated by TTP, which binds to AU-rich elements in CD36 mRNA's 3'-untranslated regions (UTRs).
- IMD repressed TTP phosphorylation, activating TTP and enhancing its binding to CD36 mRNA.
Conclusions:
- IMD attenuates macrophage foam-cell formation through TTP-mediated degradation of CD36 mRNA.
- This study uncovers a novel mechanism for IMD's anti-atherogenic action.
- A new regulatory pathway for CD36 expression in macrophages is identified.
