Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy
Frank L. van de Veerdonk, … , Claudio Costantini, Luigina Romani
Frank L. van de Veerdonk, … , Claudio Costantini, Luigina Romani
Published November 30, 2021
Citation Information: J Clin Invest. 2022;132(2):e144983. https://doi.org/10.1172/JCI144983.
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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 9

Anakinra increases CFTR activity.

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Anakinra increases CFTR activity. (A) Time course of whole-cell CFTR cur...
(A) Time course of whole-cell CFTR current densities induced by 10 μM forskolin (Fsk) + 30 μM genistein (Gen) at +50 mV in p.Phe508del-CFTR–transfected FRT cells treated with 10 μg/mL anakinra, 3 μM VX-809, or DMSO (None) for 4 hours at 37°C followed by blockade with CFTR inhibitor 172 (CFTR inh-172). The horizontal bars indicate the time period of drug application. Inset, current ramps from −100 mV to +50 mV (holding potential, −40 mV) in control condition (black trace), after application of Fsk + Gen (red trace), and after application of 1 μM CFTRinh-172 (orange trace). (B) Mean ± SEM CFTR current density measured at +50 mV induced by Fsk and Gen in cells treated with anakinra (n = 20), VX-809 (n = 10), or vehicle (n = 12). *P < 0.05, anakinra versus untreated (None), 1-way ANOVA, Bonferroni post hoc test. (C) CFTR-dependent chloride secretion measured by means of Fsk-induced increase in the Isc in HBE cells from 4 patients with CF and 1 representative control treated with anakinra for 4 hours at 37°C and mounted in Ussing chambers in the presence of CFTR inhibition (CFTR inh-172) and amiloride. **P < 0.01, anakinra-treated versus untreated (None) cells. NS, not statistically significant. Student’s t test. Data are from 2 experiments.