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Apoptosis induced by oxidized low density lipoprotein in human monocyte-derived macrophages involves CD36 and
E S Wintergerst1, J Jelk, C Rahner
1Institute of Biochemistry and Institute of Anatomy, University of Basel, Switzerland.
Insights
Oxidized LDL (OxLDL) triggers macrophage apoptosis via CD36, a key scavenger receptor. Blocking CD36 significantly reduces cell death, revealing a novel role in atherosclerosis development.
Area of Science:
- Immunology
- Cell Biology
- Cardiovascular Research
Background:
- Macrophage apoptosis is implicated in atherosclerotic lesion progression.
- Oxidized low-density lipoprotein (OxLDL) is a key factor in atherosclerosis.
- The role of scavenger receptors in OxLDL-induced macrophage death is not fully understood.
Purpose of the Study:
- To investigate the role of CD36 in oxidized LDL (OxLDL)-induced apoptosis in human macrophages.
- To elucidate the signaling pathways involved in OxLDL-mediated macrophage cell death.
Main Methods:
- Utilized human monocyte-derived macrophages treated with OxLDL.
- Employed anti-CD36 monoclonal antibodies (mAbs) SMO and OKM-5.
- Assessed apoptosis using cell counting and caspase-3 activity assays.
- Investigated the role of scavenger receptor A (SRA) by testing its ligands.
Main Results:
- Anti-CD36 mAbs significantly inhibited OxLDL-induced apoptosis (>94%).
- CD36-negative macrophages did not undergo apoptosis upon OxLDL treatment.
- Thrombospondin dose-dependently inhibited OxLDL-induced apoptosis.
- OxLDL-induced apoptosis was linked to caspase-3 activation, blocked by anti-CD36 Ig.
- Scavenger receptor A (SRA) ligands did not block OxLDL-induced apoptosis, suggesting SRA is not involved.
Conclusions:
- CD36 is essential for OxLDL-induced apoptosis in human macrophages.
- OxLDL binding to CD36 initiates a specific signaling cascade leading to caspase-3 activation and apoptosis.
- CD36 plays a novel, critical role in macrophage apoptosis relevant to atherosclerotic lesion development.
Abstract:
Macrophage death may play a crucial role in the progression of atherosclerotic lesions. Here we present evidence that CD36 is involved in oxidized LDL (OxLDL)-induced apoptosis in human monocyte-derived macrophages. Anti-CD36 mAb SMO and OKM-5 reduced the number of apoptotic cells in OxLDL-treated macrophages by more than 94%, but they did not block ceramide-triggered apoptosis. Thrombospondin inhibited the induction of apoptosis by OxLDL in a dose-dependent manner with an IC50 of 10-30 microM. OxLDL did not induce apoptosis in CD36-negative macrophages, demonstrating the essential role of this scavenger receptor in OxLDL-triggered programmed cell death. Neither anti-CD36 Ig nor thrombospondin triggered programmed cell death suggesting that binding to CD36 alone is not sufficient to initiate apoptosis. However, inhibitors of OxLDL-induced apoptosis did not block the uptake of 3H-labeled OxLDL. In contrast, acetylated LDL and polyinosinic acid, ligands of scavenger receptor A (SRA), inhibited uptake of 3H-labeled OxLDL by 65 and 49%, respectively, but did not block OxLDL-induced apoptosis, indicating that SRA is not involved in this process. OxLDL also stimulated caspase-3 activity in human macrophages. Activation of caspase-3 was blocked by anti-CD36 Ig and the caspase-3 inhibitor Z-DEVD-FMK. These results suggest that binding of OxLDL to CD36 initiates a yet unknown OxLDL-specific signaling event, which leads to the rapid activation of caspase-3 resulting in apoptosis of human macrophages. Our data demonstrate a novel role for CD36 in macrophage biology with likely consequences for the development of atherosclerotic lesions.