138. Maladaptive activation of trained immunity in the pathogenesis of Giant Cell Arteritis
Creators: name: Cantoni1, Eleonora
name: Ivan Merelli2, 3
name: Stefanoni1, Davide
name: Giordano1, Vito Federico
name: Panigada4, Maddalena
name: Alessandro Tomelleri1, 5
name: Campochiaro5, Corrado
name: Pich1, Laura Merlo
name: Natoli6, Valentina
name: Ziogas7, Athanasios
name: Domínguez-Andrés7, Jorge
name: Mazza4, Davide
name: Samuel Zambrano1, 4
name: Loffreda4, Alessia
name: Gnani4, Daniela
name: Ferrarini8, Marina
name: Ferrero8, Elisabetta
name: Vergani9, Barbara
name: Baldissera5, Elena
name: Leone9, Eugenio Biagio
name: Agresti4, Alessandra
name: Cenci4, Simone
name: Ravelli6, Angelo
name: Joosten7, Leo A. B.
name: Mihai Netea7, 10
name: Lorenzo Dagna1, 5
name: Raffaella Molteni1, 4
name: Giulio Cavalli1,4,5
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> Giant cell arteritis (GCA) is a large-vessel vasculitis characterized by inflammation of the aorta and cranial arteries, leading to rampant systemic inflammation and irreversible ischemic complications. Macrophage activation and excessive cytokine production are central to the pathogenesis of GCA, as confirmed by infiltration with myeloid cells at arterial biopsy and by the clinical efficacy of cytokine inhibitors (1). However, the mechanism responsible for this chronic inflammatory activation of monocyte/macrophages in GCA remains elusive. Trained immunity (TI) is a pro-inflammatory program induced in monocyte/macrophages upon sensing of some pathogens and characterized by immunometabolic and epigenetic changes, functionally resulting in enhanced cytokine production (2). In this study, we hypothesized that maladaptive activation of TI (i.e. in the absence of infection) may account for the development of detrimental inflammation in GCA. We specifically aimed at determining the mechanistic features of TI in GCA monocytes, and the therapeutic potential of targeting TI for the treatment of GCA. <strong>Methods:</strong> We adopted a polyfunctional approach (UHPLC-Mass Spectrometry, chromatin immunoprecipitation PCR, ATAC sequencing, RNA sequencing, ELISA assays) to compare monocytes from a large cohort clinically active GCA patients (i.e. at diagnosis or during flares) to age- and sex-matched healthy controls (HD). <strong>Results</strong>: Metabolomics studies revealed a profound immunometabolic rewiring in GCA monocytes, consistent with activation of TI (i.e. increased glycolysis, glutaminolysis through the TCA cycle, and cholesterol synthesis) (3). Epigenetic studies revealed changes in the epigenetic landscape, including H3K27Ac in enhancers of genes encoding cytokines (3), as well as increased accessibility of chromatin regions encoding for pro-inflammatory genes and effector immune mechanisRNA sequencing studies confirmed enhanced transcription of pro-inflammatory genes and pathways, both at baseline and following stimulation with LPS. ELISA assays revealed a significant increase in LPS-induced inflammatory cytokine production in GCA monocytes compared to HD, which represents the functional hallmark of TI. Furthermore, immunometabolic inhibition effectively dampened cytokine production by GCA monocytes (4). <strong>Conclusions:</strong> Altogether, our findings indicate that deregulated TI is involved in the pathogenesis of GCA and identify druggable targets for alternative and/or complementary pharmacological treatment of GCA. <strong>Disclosures:</strong> The authors declare no competing financial interests.