CD47型
泡沫电池
髓样
炎症
医学
传出细胞增多
癌症研究
免疫学
巨噬细胞
免疫系统
巨噬细胞极化
促炎细胞因子
清道夫受体
肿瘤坏死因子α
细胞生物学
生物
先天免疫系统
作者
Bhupesh Singla,Hui‐Ping Lin,WonMo Ahn,Jiean Xu,Qian Ma,Moses Sghayyer,Kunzhe Dong,Mary Cherian‐Shaw,Jiliang Zhou,Yuqing Huo,Joseph White,Gábor Csányi
出处
期刊:Cardiovascular Research
[Oxford University Press]
日期:2021-12-23
卷期号:118 (15): 3097-3111
被引量:17
摘要
Abstract Aims Inhibitors of the anti-phagocytic CD47-SIRPα immune checkpoint are currently in clinical development for a variety of haematological and solid tumours. Application of immune checkpoint inhibitors to the cardiovascular field is limited by the lack of preclinical studies using genetic models of CD47 and SIRPα inhibition. In this study, we comprehensively analysed the effects of global and cell-specific SIRPα and CD47 deletion on atherosclerosis development. Methods and results Here, we show that both SIRPα and CD47 expression are increased in human atherosclerotic arteries and primarily co-localize to CD68+ areas in the plaque region. Hypercholesterolaemic mice homozygous for a Sirpa mutant lacking the signalling cytoplasmic region (Sirpamut/mut) and myeloid cell-specific Sirpa-knockout mice are protected from atherosclerosis. Further, global Cd47−/− mice are protected from atherosclerosis but myeloid cell-specific deletion of Cd47 increased atherosclerosis development. Using a combination of techniques, we show that loss of SIRPα signalling in macrophages stimulates efferocytosis, reduces cholesterol accumulation, promotes lipid efflux, and attenuates oxidized LDL-induced inflammation in vitro and induces M2 macrophage phenotype and inhibits necrotic core formation in the arterial wall in vivo. Conversely, loss of myeloid cell CD47 inhibited efferocytosis, impaired cholesterol efflux, augmented cellular inflammation, stimulated M1 polarization, and failed to decrease necrotic core area in atherosclerotic vessels. Finally, comprehensive blood cell analysis demonstrated lower haemoglobin and erythrocyte levels in Cd47−/− mice compared with wild-type and Sirpamut/mut mice. Conclusion Taken together, these findings identify SIRPα as a potential target in atherosclerosis and suggest the importance of cell-specific CD47 inhibition as a future therapeutic strategy.
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