Henan 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.
College of Food Science and Pharmaceutical Engineering, Zaozhuang University, Zaozhuang, Shandong, China.
Biochim Biophys Acta Mol Basis Dis. 2023 Jun;1869(5):166698. doi: 10.1016/j.bbadis.2023.166698. Epub 2023 Mar 23.
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.
在动脉粥样硬化中，源自血液单核细胞的巨噬细胞有助于非解决炎症，随后引发坏死核心形成，并最终引发急性血栓性血管疾病。然而，人们对炎症细胞，尤其是巨噬细胞如何促进动脉粥样硬化知之甚少。CD68 是一种独特的 D 类清道夫受体 (SRD) 家族成员，特异性表达于单核细胞/巨噬细胞中，并在氧化低密度脂蛋白 (ox-LDL) 刺激下显著上调。然而，髓系特异性 CD68 是否以及如何影响动脉粥样硬化仍有待确定。为了确定 CD68 与动脉粥样硬化相关的重要体内作用和机制，我们在 ApoE 缺陷小鼠背景下构建了全身性和髓系特异性 CD68 缺陷小鼠。在西方饮食中，全身性和髓系限制的 CD68 缺失均可减轻 ApoE 缺陷小鼠的动脉粥样硬化，伴随免疫/炎症细胞负担和坏死核心含量减少，但动脉粥样硬化斑块中的平滑肌细胞含量增加。体外实验表明，巨噬细胞中 CD68 的缺失导致 ox-LDL 诱导的巨噬细胞凋亡减弱。此外，CD68 缺失抑制 ROS 产生，而 ROS 的去除可以显著逆转这种效应。我们进一步表明，CD68 缺失通过失活丝裂原激活蛋白激酶 (MAPK) 通路影响细胞凋亡。我们的研究结果确立了 CD68 作为巨噬细胞谱系特异性“ROS-MAPK-凋亡”轴的调节剂，为 CD68 作为冠心病危险因素的突出地位提供了一个以前未知的机制。其治疗性抑制可能为减轻心血管疾病提供一个有效的手段。
