Objective Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production. Methods Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes. Results GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production. Conclusions Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.

Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production / Cantoni, Eleonora; Merelli, Ivan; Stefanoni, Davide; Tomelleri, Alessandro; Campochiaro, Corrado; Giordano, Vito; Panigada, Maddalena; Baldissera, Elena M; Merlo Pich, Laura; Natoli, Valentina; Ziogas, Athanasios; Domínguez-Andrés, Jorge; De Luca, Giacomo; Mazza, Davide; Zambrano, Samuel; Gnani, Daniela; Ferrarini, Marina; Ferrero, Elisabetta; Agresti, Alessandra; Vergani, Barbara; Leone, Biagio Eugenio; Cenci, Simone; Ravelli, Angelo; Matucci-Cerinic, Marco; D'Alessandro, Angelo; Joosten, Leo A B; Dagna, Lorenzo; Netea, Mihai G; Molteni, Raffaella; Cavalli, Giulio. - In: RHEUMATOLOGY. - ISSN 1462-0324. - (2023). [10.1093/rheumatology/kead061]

Myelomonocytic cells in giant cell arteritis activate trained immunity programs sustaining inflammation and cytokine production

Cantoni, Eleonora
Primo
;
Stefanoni, Davide;Tomelleri, Alessandro;Campochiaro, Corrado;Giordano, Vito;De Luca, Giacomo;Mazza, Davide;Zambrano, Samuel;Cenci, Simone;Dagna, Lorenzo;Cavalli, Giulio
Ultimo
2023-01-01

Abstract

Objective Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production. Methods Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes. Results GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production. Conclusions Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.
2023
IL-6
epigenetics
immunometabolism
monocyte/macrophage
trained immunity
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/141537
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