Background/Purpose: Erdheim-Chester disease (ECD) is a chronic inflammatory disease characterized by infiltration of bone and other tissues by foamy macrophages. These cells exhibit activating mutations along the MAPK pathway, most commonly BRAFV600E, and increased production of pro-inflammatory cytokines. Although this dual neoplastic-inflammatory nature of ECD has long fascinated scientists, the mechanistic link between these two features remains elusive. We hypothesized that Trained Immunity (TI), a pro-inflammatory cell program physiologically elicited in monocytes/macrophages upon activation of the MAPK pathway, might represent the missing link between oncogenic transformation and pro-inflammatory activation in ECD. In this study, we aimed at determining the role of TI in the pathogenesis of ECD, and to evaluate the therapeutic potential of targeting this mechanism for the treatment of ECD.

Methods: We developed innovative models to study ECD pathogenesis in vitro and in vivo(ectopic expression of BRAFV600E in monocytes and hematopoietic progenitors from healthy donors cultured and/or transplanted into immunocompromised mice), as well as ex vivo (3D culture of ECD tissues in bioreactor). Mechanistic features of TI, including typical changes in cell energy metabolism and epigenetics, were investigated by assessing I) cytokine and lactate production; II) mitochondrial respiration with Seahorse flux analyzer; III) glucose and glutamine metabolism with metabolomics analyses; III) chromatin dynamics with ATAC sequencing.

Results: Activation of the MAPK pathway induced by BRAFV600E in ECD macrophages induces changes in the epigenetic landscape, cell energy metabolism, and cytokine production characteristic of TI. In particular, changes in cell energy metabolism of macrophages are characterized by increased glycolysis and glucose and glutamine metabolism. This metabolic rewiring is likely needed to sustain rampant, constitutive production of pro-inflammatory cytokines IL‑1β, IL-1α, and IL-6.

Conclusion: A role emerges for TI in the pathogenesis and pro-inflammatory activation of ECD. Since drugs targeting TI programs are already entering the clinical arena, the identification of this mechanism in the pathogenesis of ECD may translate into novel, effective treatment options for ECD patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/role-of-trained-immunity-in-the-pathogenesis-of-erdheim-chester-disease/