Anakinra restores cellular proteostasis by coupling mitochondrial redox balance to autophagy.

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

doi:10.1172/jci144983

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.

Highlights

The lung is equipped with a robust proteostasis network for handling protein folding, misfolding, unfolding, and degradation in response to mechanical and environmental stress [1]
By resorting to preclinical models in vitro and in vivo of Cystic fibrosis (CF) we have discovered that anakinra promotes IL-1R1independent autophagy through the aryl hydrocarbon receptor that, activated through the indoleamine 2,3-dioxygenase 1-kynurenine pathway, leads to NOX4-dependent mitochondrial H2O2 production and positively regulates cellular proteostasis in mice and human cells with the p.Phe508del-CFTR mutation
LC3 expression was increased in the presence of either bafilomycin (Figure 1, C and D) or chloroquine (Supplemental Figure 1), suggesting that anakinra induces an increase in autophagosomal turnover

Summary

Introduction

The lung is equipped with a robust proteostasis network for handling protein folding, misfolding, unfolding, and degradation in response to mechanical and environmental stress [1]. Autophagy selectively degrades aggregation-prone misfolded proteins such as those involved in the pathogenesis of certain neurodegenerative and lung diseases and aging [4]. In certain types of lung diseases, autophagy may provide a protective role to allow handling of misfolded protein and prevent inflammatory damage. The complexity of autophagy may prevent the full appreciation of how its modulation could be used as a therapeutic strategy in disease management. This demands for preclinical studies aimed at defining the molecular pathways of autophagy and their relevance to disease pathogenesis

Methods

Results

Conclusion