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

Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy

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.

Authors

Frank L. van de Veerdonk, Giorgia Renga, Marilena Pariano, Marina M. Bellet, Giuseppe Servillo, Francesca Fallarino, Antonella De Luca, Rossana G. Iannitti, Danilo Piobbico, Marco Gargaro, Giorgia Manni, Fiorella D’Onofrio, Claudia Stincardini, Luigi Sforna, Monica Borghi, Marilena Castelli, Stefania Pieroni, Vasileios Oikonomou, Valeria R. Villella, Matteo Puccetti, Stefano Giovagnoli, Roberta Galarini, Carolina Barola, Luigi Maiuri, Maria Agnese Della Fazia, Barbara Cellini, Vincenzo Nicola Talesa, Charles A. Dinarello, Claudio Costantini, Luigina Romani

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Figure 3

Anakinra promotes autophagy via mitochondrial H2O2.

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Anakinra promotes autophagy via mitochondrial H2O2. (A) Fluorescence ima...
(A) Fluorescence images of EGFP-LC3–transfected RAW264.7 cells exposed to anakinra and A. fumigatus conidia for 4 hours alone or upon inhibition of Atg4a or Nox4 by SiRNA. None, cells exposed to scrambled RNA. H2O2 was visualized using 10 μM DHR. Images were acquired using the Olympus BX51 fluorescence microscope and analySIS image processing software (Olympus). DAPI was used to detect nuclei. Data are from 1 representative out of 3 independent experiments. (B–E) Il1r1–/– mice were infected and treated with anakinra as in legend to Figure 1, administered SiNox4 or scrambled peptide, and assessed for fungal growth (log10 CFU) (B), histology [PAS staining] I, p62 immunoblotting (D), and LC3 immunofluorescence staining (E) in lung cell lysates or lungs. Insets in C show the bronchoalveolar lavage morphometry with the percentage of polymorphonuclear cells (PMNs) and an arrow indicating the appearance of fungi in SiNox4-treated mice. For CFU, lung staining, and immunoblotting, data are representative of 1 out of 2 independent experiments. Each independent in vivo experiment includes 4 mice per group. *P < 0.05, SiNox4-treated versus scrambled peptide. One-way ANOVA, Bonferroni post hoc test. Effectiveness of silencing was verified by quantitative RT-PCR analysis at 24 hours (Supplemental Figure 9).