Anakinra Activates Superoxide Dismutase 2 to Mitigate Inflammasome Activity
Open Access
- 18 June 2021
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 22 (12), 6531
- https://doi.org/10.3390/ijms22126531
Abstract
Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.Funding Information
- Italian Cystic Fibrosis Research Foundation (FFC#22/2014)
This publication has 37 references indexed in Scilit:
- Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeuticsAmerican Journal of Physiology-Heart and Circulatory Physiology, 2013
- Treating inflammation by blocking interleukin-1 in a broad spectrum of diseasesNature Reviews Drug Discovery, 2012
- CD4+ T cell vaccination overcomes defective cross-presentation of fungal antigens in a mouse model of chronic granulomatous diseaseJCI Insight, 2012
- Mitochondria and the Autophagy–Inflammation–Cell Death Axis in Organismal AgingScience, 2011
- Protein stability of mitochondrial superoxide dismutase SOD2 is regulated by USP36Journal of Cellular Biochemistry, 2011
- Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to StressMolecular Cell, 2010
- Superoxide dismutases, lung function and bronchial responsiveness in a general populationEuropean Respiratory Journal, 2009
- PGC-1α: a key regulator of energy metabolismAdvances in Physiology Education, 2006
- Superoxide Dismutases in the Lung and Human Lung DiseasesAmerican Journal of Respiratory and Critical Care Medicine, 2003
- Mitochondrial Complex I Inhibitor Rotenone Induces Apoptosis through Enhancing Mitochondrial Reactive Oxygen Species ProductionOnline Journal of Public Health Informatics, 2003