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 4

Anakinra colocalizes with AhR in Il1r1–/– cells.

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Anakinra colocalizes with AhR in Il1r1–/– cells. (A) Immunofluorescence ...
(A) Immunofluorescence imaging of cellular localization of FITC-anakinra in alveolar macrophages, isolated from naive C57BL/6 or Il1r1–/– mice, primed with 100 ng/mL LPS for 2 hours at 37°C, and exposed to 10 μg/mL FITC-anakinra for 60 minutes. (B) Immunofluorescence analysis of FITC-anakinra in Il1r1–/– cells exposed to FITC-anakinra at 30 and 60 minutes in the presence of 5 μM cytochalasin D. Insets, percentage positive cells. (C) Il1r1–/– MEF cells were treated with 10 μg/mL anakinra for 0, 2, and 4 hours and assessed for AhR and IL1Ra expression by immunoblotting with specific antibodies. (D) Immunofluorescence imaging of alveolar macrophages from naive C57BL/6 and Il1r1–/– mice primed with 100 ng/mL LPS for 2 hours at 37°C, exposed to 10 μg/mL FITC-anakinra for 60 minutes, and stained with anti-AhR antibody. (E) Immunofluorescence imaging of MEF cells stained with anti-AhR antibody and DAPI and exposed to 10 μg/mL FITC-anakinra for 60 minutes. (F) Il1r1–/– MEF cells were treated with 10 μg/mL anakinra, lysed, immunoprecipitated with anti-AhR antibody, and assessed for IL1Ra and AhR expression by immunoblotting with specific antibodies. None, untreated cells. Representative images, acquired with a fluorescent microscope (BX51), and immunoblots from 2 independent experiments are shown. DAPI was used to detect nuclei. Sections were examined using a Zeiss Axio Observer Z1.