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.
Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
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;Puccetti, Matteo;Giovagnoli, Stefano;Galarini, Roberta;Della Fazia, Maria Agnese;Cellini, Barbara;Talesa, Vincenzo Nicola;Costantini, Claudio;Romani, Luigina;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;Puccetti, Matteo;Giovagnoli, Stefano;Galarini, Roberta;Cellini, Barbara;Talesa, Vincenzo Nicola;Costantini, Claudio;Romani, Luigina
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 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
