| Title: |
Interferon gamma rebalances immunopathological signatures in chronic granulomatous disease through metabolic rewiring |
| Authors: |
Bruno, M.; Kröger, C.; Ferreira, A. V.; Zhang, B.; Röring, R. J.; Liu, R.; van der Made, C. I.; van Rhijn, N.; Groh, L.; Klück, V.; Janssen, N. A. F.; Li, W.; Rosati, D.; Alaswad, A.; Tercan, H.; Saiz, J.; Gonzalez-Riano, C.; van Uelft, M.; Gaal, O. I.; Müller, S.; Ferreira, H. J.; Warnat-Herresthal, S.; Becker, M.; Holsten, L.; Kraut, M.; Schulte-Schrepping, J.; Bonaguro, L.; Händler, K.; Cunha, C.; Schmolz, M.; Schultze, J. L.; Joosten, L. A. B.; Barbas, C.; Netea, M. G.; Li, Y.; Aschenbrenner, A. C.; Carvalho, Agostinho; van de Veerdonk, F. L. |
| Publisher Information: |
American Society of Hematology |
| Publication Year: |
2025 |
| Collection: |
Universidade of Minho: RepositóriUM |
| Subject Terms: |
Ciências Médicas::Ciências da Saúde; Saúde de qualidade |
| Description: |
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by recurrent life-threatening infections and hyperinflammatory complications. It is caused by mutations in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex and the consequent loss of reactive oxygen species (ROS) production. Recombinant human interferon gamma (rIFN-γ) prophylaxis reduces the risk of severe infections, but the mechanisms behind its efficacy in CGD are still an open question, as it does not restore NADPH oxidase-dependent ROS production. Here, we demonstrate that the innate immune cells of patients with CGD are transcriptionally and functionally reprogrammed to a hyperactive inflammatory status, displaying an impaired in vitro induction of trained immunity. CGD monocytes have reduced intracellular amino acid concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatments with IFN-γ restored these metabolic defects and reduced excessive interleukin 1β (IL-1β) and IL-6 production in response to fungal stimuli in CGD monocytes. These data suggest that prophylactic rIFN-γ modulates the metabolic status of innate immune cells in CGD. These data shed light on the effects of NADPH oxidase-derived ROS deficiency to the metabolic programs of immune cells and pose the basis for targeting this immunometabolic axis, potentially beyond CGD, with IFN-γ immunotherapy. ; A.C. and C.C. were supported by FCT through the grants UIDB/50026/2020, UIDP/ 50026/2020, LA/P/0050/2020, PTDC/MED-OUT/1112/2021 to A.C. and CEECIND/04058/2018 and 2022.06674.PTDC to C.C., the “la Caixa” Foundation under the agreement LCF/PR/HR22/52420003 (MICROFUN) to C.C., and the “la Caixa” Foundation and FCT under the agreement LCF/PR/HR17/52190003 (TRANS-CPA) to A.C. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Host directed medicine in invasive fungal infection (847507); ICVS/3B's - Associate Laboratory (UIDB/50026/2020); ICVS/3B's - Associate Laboratory (UIDP/50026/2020); ICVS/3B’s - Associate Laboratory, Life and Health Sciences Research Institute / Biomaterials, Biodegradables and Biomimetics Research Group (LA/P/0050/2020); Immunometabolic Regulation of Granulomatous Inflammation in Sarcoidosis (PTDC/MED-OUT/1112/2021); A synthetic biology approach to the microbiome-metabolome crosstalk in respiratory fungal diseases (CEECIND/04058/2018/CP1581/CT0015); Metabolic Control of Immune Cell Function in Respiratory Fungal Disease (2022.06674.PTDC); LCF/PR/HR22/ 52420003; https://ashpublications.org/bloodadvances/article/9/20/5306/546229/; https://hdl.handle.net/1822/98324 |
| DOI: |
10.1182/bloodadvances.2025016213 |
| Availability: |
https://hdl.handle.net/1822/98324; https://doi.org/10.1182/bloodadvances.2025016213 |
| Rights: |
openAccess ; http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Accession Number: |
edsbas.DDD0D91 |
| Database: |
BASE |