{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:43:01Z","timestamp":1790905381688,"version":"4.1.0"},"reference-count":35,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T00:00:00Z","timestamp":1623974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008385","name":"Italian Cystic Fibrosis Research Foundation","doi-asserted-by":"publisher","award":["FFC#22\/2014"],"award-info":[{"award-number":["FFC#22\/2014"]}],"id":[{"id":"10.13039\/501100008385","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/ijms22126531","type":"journal-article","created":{"date-parts":[[2021,6,18]],"date-time":"2021-06-18T04:10:47Z","timestamp":1623989447000},"page":"6531","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Anakinra Activates Superoxide Dismutase 2 to Mitigate Inflammasome Activity"],"prefix":"10.3390","volume":"22","author":[{"given":"Marilena","family":"Pariano","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3910-503X","authenticated-orcid":false,"given":"Stefania","family":"Pieroni","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossana G.","family":"Iannitti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6337-5999","authenticated-orcid":false,"given":"Monica","family":"Borghi","sequence":"additional","affiliation":[{"name":"Department of Medicine and 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Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiorella","family":"D\u2019Onofrio","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina M.","family":"Bellet","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Stincardini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Agnese","family":"Della-Fazia","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7960-7689","authenticated-orcid":false,"given":"Giuseppe","family":"Servillo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank L.","family":"van de Veerdonk","sequence":"additional","affiliation":[{"name":"Department of Medicine, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1433-7830","authenticated-orcid":false,"given":"Claudio","family":"Costantini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigina","family":"Romani","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.immuni.2019.08.005","article-title":"Inflammasomes: Threat-Assessment Organelles of the Innate Immune System","volume":"51","author":"Evavold","year":"2019","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/nri.2016.151","article-title":"Homeostasis-altering molecular processes as mechanisms of inflammasome activation","volume":"17","author":"Liston","year":"2017","journal-title":"Nat. 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