Cathepsins drive anti-inflammatory activity by regulating autophagy and mitochondrial dynamics in macrophage foam cells

Tommy Weiss-Sadan, David Maimoun, Diana Oelschlagel, Farnusch Kaschani, Danny Misiak, Hanmant Gaikwad, Yael Ben-Nun, Emmanuelle Merquiol, Adi Anaki, Darya Tsvirkun, Markus Kaiser, Patrick Michl, Israel Gotsman, Galia Blum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)550-572
Number of pages23
JournalCellular Physiology and Biochemistry
Volume53
Issue number3
DOIs
StatePublished - 2019

Bibliographical note

Publisher Copyright:
© 2019 The Author(s).

Keywords

  • Autophagy
  • Cathepsins
  • Macrophages
  • Mitochondrial dynamics
  • Vascular inflammation

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