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Updated: Aug 5, 2025
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Myeloid-restricted CD68 deficiency attenuates atherosclerosis via inhibition of ROS-MAPK-apoptosis axis
Liangwei Duan1, Yucong Zhao1, Jing Jia1
1Henan Key Laboratory of Immunology and Targeted Drugs, Xinxiang Medical University, Xinxiang, Henan, China; Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China.
Insights
CD68 deficiency in macrophages reduces atherosclerosis by inhibiting the ROS-MAPK-apoptosis pathway. This finding reveals a novel mechanism linking CD68 to cardiovascular disease risk.
Area of Science:
- Immunology
- Cardiovascular Biology
- Molecular Medicine
Background:
- Macrophages fuel atherosclerosis through non-resolving inflammation.
- The role of CD68, a macrophage-specific scavenger receptor, in atherosclerosis is largely undefined.
- CD68 expression increases with oxidized low-density lipoprotein (ox-LDL) exposure.
Purpose of the Study:
- To investigate the in vivo role and mechanism of myeloid-specific CD68 in atherosclerosis.
- To determine if CD68 deficiency impacts atherosclerotic plaque development and macrophage apoptosis.
Main Methods:
- Generated global and myeloid-specific CD68-deficient mice on an ApoE-null background.
- Administered a Western diet to induce atherosclerosis.
- Performed in vitro studies on macrophages to assess ox-LDL-induced apoptosis, ROS production, and MAPK pathway activation.
Main Results:
- Global and myeloid CD68 deletion attenuated atherosclerosis in mice.
- Reduced immune/inflammatory cell burden and necrotic core content were observed.
- CD68 deficiency decreased ox-LDL-induced macrophage apoptosis by suppressing ROS production and inactivating the MAPK pathway.
Conclusions:
- CD68 acts as a macrophage-specific regulator of the ROS-MAPK-apoptosis axis in atherosclerosis.
- CD68 deficiency mitigates atherosclerosis development and progression.
- Therapeutic inhibition of CD68 may offer a novel strategy for cardiovascular disease treatment.
Abstract:
In atherosclerosis, macrophages derived from blood monocytes contribute to non-resolving inflammation, which subsequently primes necrotic core formation, and ultimately triggers acute thrombotic vascular disease. Nevertheless, little is known about how inflammatory cells, especially the macrophages fuel atherosclerosis. CD68, a unique class D scavenger receptor (SRD) family member, is specifically expressed in monocytes/macrophages and remarkably up-regulated upon oxidized low-density lipoprotein (ox-LDL) stimulation. Nonetheless, whether and how myeloid-specific CD68 affects atherosclerosis remains to be defined. To determine the essential in vivo role and mechanism linking CD68 to atherosclerosis, we engineered global and myeloid-specific CD68-deficient mice on an ApoE-null background. On Western diet, both the mice with global and the myeloid-restricted deletion of CD68 on ApoE-null background attenuated atherosclerosis, accompanied by diminished immune/inflammatory cell burden and necrotic core content, but increased smooth muscle cell content in atherosclerotic plaques. In vitro experiments revealed that CD68 deficiency in macrophages resulted in attenuated ox-LDL-induced macrophage apoptosis. Additionally, CD68 deficiency suppressed ROS production, while removal of ROS can markedly reversed this effect. We further showed that CD68 deficiency affected apoptosis through inactivation of the mitogen-activated protein kinase (MAPK) pathway. Our findings establish CD68 as a macrophage lineage-specific regulator of "ROS-MAPK-apoptosis" axis, thus providing a previously unknown mechanism for the prominence of CD68 as a risk factor for coronary artery disease. Its therapeutic inhibition may provide a potent lever to alleviate the cardiovascular disease.
