期刊
CIRCULATION RESEARCH
卷 122, 期 10, 页码 1369-1384出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.117.312333
关键词
cholesterol; inflammation; macrophage; mitochondria; oxysterols
资金
- Fondation ARC (Association pour la Recherche sur le Cancer) [RAC15014AAA]
- Austrian Science Fund [W1226 DK-MCD]
- Inserm Atip-Avenir program
- association VML (Vaincre les Maladies Lysosomales)
- European Marie Curie Career Integration Grant [CIG-630926]
- Agence Nationale de la Recherche [ANR-14-CE12-0017-01]
- Agence Nationale de la Recherche (ANR) [ANR-14-CE12-0017] Funding Source: Agence Nationale de la Recherche (ANR)
Rationale: Macrophages face a substantial amount of cholesterol after the ingestion of apoptotic cells, and the LIPA (lysosomal acid lipase) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. Objective: Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. Methods and Results: We show that LIPA inhibition causes a defective efferocytic response because of impaired generation of 25-hydroxycholesterol and 27-hydroxycholesterol. Reduced synthesis of 25-hydroxycholesterol after LIPA inhibition contributed to defective mitochondria-associated membrane leading to mitochondrial oxidative stress-induced NLRP3 (NOD-like receptor family, pyrin domain containing) inflammasome activation and caspase-1-dependent Rac1 (Ras-related C3 botulinum toxin substrate 1) degradation. A secondary event consisting of failure to appropriately activate liver X receptor-mediated pathways led to mitigation of cholesterol efflux and apoptotic cell clearance. In mice, LIPA inhibition caused defective clearance of apoptotic lymphocytes and stressed erythrocytes by hepatic and splenic macrophages, culminating in splenomegaly and splenic iron accumulation under hypercholesterolemia. Conclusions: Our findings position lysosomal cholesterol hydrolysis as a critical process that prevents metabolic inflammation by enabling efficient macrophage apoptotic cell clearance.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据