Cathepsins Drive Anti-Inflammatory Activity by Regulating Autophagy and Mitochondrial Dynamics in Macrophage Foam Cells.
Cathepsins Drive Anti-Inflammatory Activity by Regulating Autophagy and Mitochondrial Dynamics in Macrophage Foam Cells.
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DOI：
10.33594/000000157
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发表时间：
2019-09
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通讯作者：
Tommy Weiss-Sadan;David Maimoun;D. Oelschlagel;F. Kaschani;Danny Misiak;Hanmant Gaikwad;Y. Ben-Nun;E. Merquiol;Adi Anaki;Darya Tsvirkun;M. Kaiser;P. Michl;I. Gotsman;G. Blum
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文献类型：
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作者：
Tommy Weiss-Sadan;David Maimoun;D. Oelschlagel;F. Kaschani;Danny Misiak;Hanmant Gaikwad;Y. Ben-Nun;E. Merquiol;Adi Anaki;Darya Tsvirkun;M. Kaiser;P. Michl;I. Gotsman;G. Blum
背景/目的 动脉粥样硬化是大多数心血管事件的基础，是由无法解决的炎症引起的。大量证据表明自噬功能障碍是这种炎症性疾病的核心，但这种功能障碍的基础尚不完全清楚。方法利用载脂巨噬细胞的体外模型、基于活性的探针和高通量技术，我们研究了半胱氨酸蛋白酶组织蛋白酶在自噬中的作用。结果我们发现组织蛋白酶活性受到氧化脂质的抑制，并且组织蛋白酶在自噬-溶酶体降解途径中具有不可或缺的作用。因此，组织蛋白酶功能的丧失导致自噬紊乱。鸟枪法蛋白质组学证实了自噬功能障碍，并揭示了组织蛋白酶 L 在假定的组织蛋白酶降解网络中的关键作用。在生理水平上，组织蛋白酶抑制导致线粒体应激，进而转化为氧化代谢受损、活性氧过度产生以及由 ATF4-CHOP 转录因子驱动的细胞应激反应激活。此外，这些细胞的转录组分析揭示了与炎症巨噬细胞表型（又名 M1 巨噬细胞）的一些遗传相似性以及炎症细胞因子表达的增加。结论我们的数据强调了组织蛋白酶对于线粒体质量控制机制和改善血管炎症的重要性。
BACKGROUND/AIMS Atherosclerosis underlies the majority of cardiovascular events, consequent to non-resolving inflammation. Considerable evidence implicates autophagy dysfunction at the core of this inflammatory condition, but the basis of this dysfunction is not fully understood. METHODS Using an in vitro model of lipid-laden macrophages, activity-based probes and high-throughput techniques, we studied the role of the cysteine proteases cathepsins in autophagy. RESULTS We showed that cathepsin activity is suppressed by oxidized lipids and that cathepsin has an indispensable role in the autophagy-lysosomal degradation pathway. Accordingly, loss of cathepsin function resulted in autophagy derangement. Shotgun proteomics confirmed autophagy dysfunction and unveiled a pivotal role of cathepsin L in a putative cathepsin degradation network. At the physiological level, cathepsin inhibition resulted in mitochondrial stress, which translated into impaired oxidative metabolism, excessive production of reactive oxygen species and activation of the cellular stress response, driven by ATF4-CHOP transcription factors. In addition, transcriptomic analysis of these cells uncovered some genetic similarities with the inflammatory macrophage phenotype (a.k.a M1 macrophages) and increased expression of inflammatory cytokines. CONCLUSION Our data highlight the importance of cathepsins for mitochondrial quality control mechanisms and amelioration of vascular inflammation.