Istituto Zooprofilattico Sperimentale dell'Umbria e delle Marche ''Togo Rosati''

Authors   van de Veerdonk F L, Renga G, … , Galarini R, Barola C, Maiuri L, della Fazia M A, Cellini B, Talesa V N, Dinarello C A, Costantini C, Romani L

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 IL-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 activated 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 antiinflammatory 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.

Publish Date     2022

Volume      132 (2)

ISSN      1558-8238

DOI     doi.org/10.1172/JCI144983

URL    https://www.jci.org/articles/view/144983  

Journal    Journal of Clinical Investigation

Pages    e144983

PMID     34847078