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oxLDL antibody inhibits MCP-1 release in monocytes/macrophages by regulating Ca2+ /K+ channel flow
Jinyu Su1, Hui Zhou1, Xianyan Liu1
1Department of Pathophysiology, Key Lab for Shock and Microcirculation Research of Guangdong, Southern Medical University, Guangzhou, China.
Abstract:
oxLDL peptide vaccine and its antibody adoptive transferring have shown a significantly preventive or therapeutic effect in atherosclerotic animal model. The molecular mechanism behind this is obscure. Here, we report that oxLDL induces MCP-1 release in monocytes/macrophages through their TLR-4 (Toll-like receptor 4) and ERK MAPK pathway and is calcium/potassium channel-dependent. Using blocking antibodies against CD36, TLR-4, SR-AI and LOX-1, only TLR-4 antibody was found to have an inhibitory effect and ERK MAPK-specific inhibitor (PD98059) was found to have a dramatic inhibitory effect compared to inhibitors of other MAPK group members (p38 and JNK MAPKs) on oxLDL-induced MCP-1 release. The release of cytokines and chemokines needs influx of extracellular calcium and imbalance of efflux of potassium. Nifedipine, a voltage-dependent calcium channel (VDCC) inhibitor, and glyburide, an ATP-regulated potassium channel (K+ATP ) inhibitor, inhibit oxLDL-induced MCP-1 release. Potassium efflux and influx counterbalance maintains the negative potential of macrophages to open calcium channels, and our results suggest that oxLDL actually induces the closing of potassium influx channel - inward rectifier channel (Kir ) and ensuing the opening of calcium channel. ERK MAPK inhibitor PD98059 inhibits oxLDL-induced Ca2+ /Kir channel alterations. The interfering of oxLDL-induced MCP-1 release by its monoclonal antibody is through its FcγRIIB (CD32). Using blocking antibodies against FcγRI (CD64), FcγRIIB (CD32) and FcγRIII (CD16), only CD32 blocking antibody was found to reverse the inhibitory effect of oxLDL antibody on oxLDL-induced MCP-1 release. Interestingly, oxLDL antibody specifically inhibits oxLDL-induced ERK MAPK activation and ensuing Ca2+ /Kir channel alterations, and MCP-1 release. Thus, we found a molecular mechanism of oxLDL antibody on inhibition of oxLDL-induced ERK MAPK pathway and consequent MCP-1 release.
Insights
Oxidized LDL (oxLDL) triggers MCP-1 release via Toll-like receptor 4 and ERK MAPK pathways, involving calcium and potassium channels. oxLDL antibodies inhibit this by targeting FcγRIIB, revealing a therapeutic mechanism for atherosclerosis.
Area of Science:
- Immunology
- Cardiovascular Biology
- Molecular Medicine
Background:
- Oxidized low-density lipoprotein (oxLDL) plays a key role in atherosclerosis.
- oxLDL peptide vaccines and antibody therapies show therapeutic potential, but mechanisms are unclear.
Purpose of the Study:
- To elucidate the molecular mechanism by which oxLDL induces MCP-1 release.
- To investigate the role of Toll-like receptor 4 (TLR-4), ERK MAPK, and ion channels in oxLDL-induced MCP-1 release.
- To determine how oxLDL antibodies exert their inhibitory effects.
Main Methods:
- Monocytes/macrophages were stimulated with oxLDL.
- Inhibitors for TLR-4, ERK MAPK (PD98059), p38, JNK, calcium channels (Nifedipine), and potassium channels (Glyburide) were used.
- Blocking antibodies against CD36, TLR-4, SR-AI, LOX-1, FcγRI, FcγRIIB, and FcγRIII were employed.
- MCP-1 release, ERK MAPK activation, and ion channel activity were measured.
Main Results:
- oxLDL induces MCP-1 release via TLR-4 and ERK MAPK, dependent on calcium influx and potassium efflux.
- Inhibition of TLR-4, ERK MAPK, VDCC, and K+ATP channels significantly reduced MCP-1 release.
- oxLDL closes inward rectifier potassium channels (Kir) and opens calcium channels.
- oxLDL antibodies inhibit oxLDL-induced MCP-1 release by targeting FcγRIIB (CD32), suppressing ERK MAPK activation and ion channel alterations.
Conclusions:
- oxLDL induces MCP-1 release through a pathway involving TLR-4, ERK MAPK, and altered calcium/potassium channel function.
- oxLDL antibodies exert therapeutic effects by inhibiting this pathway via FcγRIIB engagement.
- This study reveals a novel molecular mechanism for oxLDL-induced inflammation and antibody-based therapies in atherosclerosis.
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