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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. [ABSTRACT FROM AUTHOR]

The article presents a case study which characterized the functional and metabolic outcomes of an activating Kirsten rat sarcoma viral oncogene homologue (KRAS) mutation in a patient affected by Langerhans-related histiocytosis. Topics include case of a patient with articular, pituitary and skin involvement, comparison between the supernatant of tissue lesions and tissue culture medium, and clinical effectiveness MAPK pathway inhibition with selective MEK inhibitors in histiocytosis patients.

Erdheim‐Chester disease (ECD) is a rare histiocytosis characterized by infiltration of multiple tissues by CD68+ foamy Mϕs (or 'histiocytes'). Clinical manifestations arise from mass‐forming lesions or from tissue and systemic inflammation. ECD histiocytes harbor oncogenic mutations along the MAPK‐kinase signaling pathway (BRAFV600E in more than half of the patients), and secrete abundant pro‐inflammatory cytokines and chemokines. Based on these features, ECD is considered an inflammatory myeloid neoplasm, and is accordingly managed with targeted kinase inhibitors or immunosuppressive and cytokine‐blocking agents. Evidence is emerging that maladaptive metabolic changes, particularly up‐regulated glycolysis, represent an additional, mutation‐driven feature of ECD histiocytes, which sustains deregulated and protracted pro‐inflammatory activation and cytokine production. Besides translational relevance to the management of ECD patients and to the development of new therapeutic approaches, recognition of ECD as a natural human model of chronic, maladaptive Mϕ activation instructs the understanding of Mϕ dysfunction in other chronic inflammatory conditions. [ABSTRACT FROM AUTHOR]