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POS0492 MALADAPTIVE ACTIVATION OF TRAINED IMMUNITY IN THE PATHOGENESIS AND TREATMENT OF GIANT CELL ARTERITIS

2022; BMJ; Volume: 81; Issue: Suppl 1 Linguagem: Inglês

10.1136/annrheumdis-2022-eular.1540

1468-2060

Eleonora Cantoni, I. Merelli, D. Stefanoni, A. Tomelleri, C. Campochiaro, E. Baldissera, Jorge Domínguez‐Andrés, M. Matucci-Cerinic, A. D’alessandro, L. Dagna, M. Netea, Raffaella Molteni, G. Cavalli,

Inflammasome and immune disorders

Background Trained immunity (TI) is a de facto innate immune memory program of monocyte/macrophages, mechanistically characterized by immunometabolic and epigenetic changes sustaining persistent inflammatory activation with enhanced cytokine production. TI evolved as a protective mechanism against infections; however, maladaptive activation can cause detrimental inflammation and might be implicated in the pathogenesis of rheumatic and musculoskeletal diseases (RMDs). Objectives In this study, we investigated the role of maladaptive TI in the pathogenesis of Giant Cell Arteritis (GCA), a disease characterized by aberrant macrophage activation. Methods Monocytes from a large cohort of clinically active GCA patients (ie, at diagnosis or during disease flares, n=20) and from age- and sex-matched healthy donors were subjected to polyfunctional determinations, including intracellular metabolomics, chromatin immunoprecipitation PCR, ATAC and RNA sequencing, and cytokine production assays. Arteries from GCA patients were evaluated with immunohistochemistry (IHC) to assess immunometabolic activation. Pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) was evaluated ex vivo as a therapeutic strategy to suppress cytokine production. Results GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included typical immunometabolic changes (eg, increased glycolysis and glutaminolysis through the TCA cycle), epigenetic changes promoting transcription of genes governing pro-inflammatory activation, and enhanced IL-6 production upon inflammatory challenge. IHC revealed that GCA lesions are highly glycolytic microenvironments, and pharmacologic inhibition of glycolysis with 2-deoxy-glucose effectively dampened IL-6 production. Conclusion This study reveals the deleterious potential of maladaptive TI in the pathogenesis of GCA, and the therapeutic potential of inhibiting TI for the treatment of this condition. Acknowledgements This study was supported by the Foundation for Research in Rheumatology (FOREUM Career Award 2020 to GC). GC is also supported by AIRC under MFAG 2018 (ID. 22136 project – P.I. Giulio Cavalli); EHA (European Haematology Association Physician Scientist Grant 2021); Italian Ministry of Health (GR-2018-12366385); SIMI (Italian Society of Internal Medicine, G. Licata Award 2021). Disclosure of Interests Eleonora Cantoni: None declared, Ivan Merelli: None declared, Davide Stefanoni: None declared, Alessandro Tomelleri: None declared, Corrado Campochiaro: None declared, Elena Baldissera: None declared, Jorge Dominguez Andres: None declared, Marco Matucci-Cerinic: None declared, Angelo D’Alessandro: None declared, Lorenzo Dagna Speakers bureau: SANOFI, NOVARTIS, SOBI, Mihai Netea: None declared, Raffaella Molteni: None declared, Giulio Cavalli: None declared.