Presenter of 1 Presentation
RECOMBINANT INTERFERON GAMMA RESTORES ALTERED IMMUNOMETABOLISM IN CGD
Abstract
Background and Aims
Chronic granulomatous disease (CGD) is characterized by recurrent life-threatening infections and hyperinflammatory complications.It is caused by mutations in the NADPH oxidase complex and the consequent loss of reactive oxygen species (ROS) production. Recombinant human interferon gamma (rIFNγ) is used as prophylaxis to reduce the risk of severe infections, but the mechanisms behind its efficacy in CGD are still unknown.
Methods
We compared the immune and metabolic profile of immmune cells from CGD patients with healthy controls using scRNAseq analysis, ATACseq profiling, ELISA, proteomics, Seahorse and metabolomics. Finally, we investigated the effect of in vitro rIFNγ treatment on some of those parameters.
Results
We found that innate immune myeloid cells from CGD patients are epigenetically and functionally reprogrammed to have a hyperactivated immune status. In parallel, they present an impaired in vitro induction of trained immunity. CGD monocytes have deficient intracellular amino acids levels and have profound functional metabolic defects, both at the glycolytic and mitochondrial level. In vitro treatment with rIFNγ restored these myeloid metabolic defects and reduced abnormal IL-1β and IL-6 production in response to fungal stimuli in CGD monocytes, suggesting that prophylactic rIFNγ efficacy in CGD patients has a metabolic basis.
Conclusions
Learning more about the immunometabolic defects underlying diseases will not only give new insight into their pathogenesis but, beyond CGD, might open doors for efficient and targeted immunotherapy aimed at correcting these defects. In conclusion, our findings address a new avenue of research exploring the consequences of a defective NADPH oxidase complex in the metabolic rewiring of immune cells.