1. Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
- Author
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van de Veerdonk, Frank L, Renga, Giorgia, Pariano, Marilena, Bellet, Marina M, Servillo, Giuseppe, Fallarino, Francesca, De Luca, Antonella, Iannitti, Rossana G, Piobbico, Danilo, Gargaro, Marco, Manni, Giorgia, D'Onofrio, Fiorella, Stincardini, Claudia, Sforna, Luigi, Borghi, Monica, Castelli, Marilena, Pieroni, Stefania, Oikonomou, Vasileios, Villella, Valeria R, Puccetti, Matteo, Giovagnoli, Stefano, Galarini, Roberta, Barola, Carolina, Maiuri, Luigi, Della Fazia, Maria Agnese, Cellini, Barbara, Talesa, Vincenzo Nicola, Dinarello, Charles A, Costantini, Claudio, Romani, Luigina, van de Veerdonk, Frank L, Renga, Giorgia, Pariano, Marilena, Bellet, Marina M, Servillo, Giuseppe, Fallarino, Francesca, De Luca, Antonella, Iannitti, Rossana G, Piobbico, Danilo, Gargaro, Marco, Manni, Giorgia, D'Onofrio, Fiorella, Stincardini, Claudia, Sforna, Luigi, Borghi, Monica, Castelli, Marilena, Pieroni, Stefania, Oikonomou, Vasileio, Villella, Valeria R, Puccetti, Matteo, Giovagnoli, Stefano, Galarini, Roberta, Barola, Carolina, Maiuri, Luigi, Della Fazia, Maria Agnese, Cellini, Barbara, Talesa, Vincenzo Nicola, Dinarello, Charles A, Costantini, Claudio, and Romani, Luigina
- 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 - 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.
- Published
- 2022