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Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
- Source :
- The Journal of Clinical Investigation, Population and Environment, 132, Population and Environment, 132, 2
- Publication Year :
- 2022
-
Abstract
- Autophagy selectively degrades aggregation-prone misfolded proteins caused by defective cellular proteostasis. However, the complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. Here we define a molecular pathway through which recombinant interleukin-1 receptor antagonist (IL-1Ra, anakinra) affects cellular proteostasis independently from the IL-1 receptor (IL-1R1). Anakinra promoted H2O2-driven autophagy through a xenobiotic sensing pathway involving the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, transcriptionally activates NADPH Oxidase 4 independent of the IL-1R1. By coupling the mitochondrial redox balance to autophagy, anakinra improved the dysregulated proteostasis network in murine and human cystic fibrosis. We anticipate that anakinra may represent a therapeutic option in addition to its IL-1R1 dependent anti-inflammatory properties by acting at the intersection of mitochondrial oxidative stress and autophagy with the capacity to restore conditions in which defective proteostasis leads to human disease.
- Subjects :
- Fungal infection
Male
medicine.drug_class
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
medicine.disease_cause
Mice
Fungal infections
All institutes and research themes of the Radboud University Medical Center
medicine
Autophagy
Animals
Receptor
Mice, Knockout
Inflammation
Anakinra
Infectious disease
NADPH oxidase
biology
Chemistry
General Medicine
Aryl hydrocarbon receptor
Receptor antagonist
Cell biology
Mitochondria
Interleukin 1 Receptor Antagonist Protein
Oxidative Stress
Proteostasis
biology.protein
Female
Oxidation-Reduction
Oxidative stress
medicine.drug
Research Article
Subjects
Details
- ISSN :
- 01990039
- Volume :
- 132
- Database :
- OpenAIRE
- Journal :
- Population and Environment
- Accession number :
- edsair.doi.dedup.....16552ad30ba3e54a3558812ade38c7ac