Presenter of 1 Presentation
O015 - MALADAPTIVE ACTIVATION OF TRAINED IMMUNITY IN THE PATHOGENESIS AND TREATMENT OF GIANT CELL ARTERITIS (ID 168)
Abstract
Background and Aims
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 RMDs. In this study, we investigated the role of maladaptive TI in the pathogenesis of Giant Cell Arteritis (GCA).
Methods
Monocytes from a large cohort of clinically active GCA patients (ie, at diagnosis or during disease flares, n=19) 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. Tissue biopsies 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.
Conclusions
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.