Trained immunity (TI) is a pro-inflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and characterized by immunometabolic and epigenetic changes enhancing cytokine production. Maladaptive activation of TI (i.e., in the absence of infection) might result in detrimental inflammation and disease development; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. Here, we reveal oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, ECD, characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production). Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mTOR signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyper-inflammatory responses. In ECD patients, effective therapeutic strategies contrast this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (i.e., glycolysis) effectively dampens cytokine production by myeloid cells. This study reveals the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms, and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.
Riccardo Biavasco, Raffaella Molteni, Davide Stefanoni, Travis Nemkov, Mihai G Netea, Jorge Domínguez-Andrés, Rob Jw Arts, Ivan Merelli, Davide Mazza, Samuel Zambrano, Maddalena Panigada, Eleonora Cantoni, Isak Tengesdal, Philippe Maksud, Francesco Piras, Giacomo De Luca, Laura Cassina, Gianfranco Distefano, Alessia Loffreda, Daniela Gnani, Claudio Doglioni, Alessandro Tomelleri, Corrado Campochiaro, Leo Joosten, Charles A Dinarello, Anna Kajaste-Rudnitski, Julien Haroche, Simone Cardaci, Simone Cenci, Lorenzo Dagna, Marina Ferrarini, Elisabetta Ferrero, Alessandra Boletta, Angelo D'Alessandro, Eugenio Montini, Giulio Cavalli