TY  - JOUR
AU  - Bruno, Mariolina
AU  - Kröger, Charlotte
AU  - Ferreira, Anaísa V
AU  - Zhang, Bowen
AU  - Röring, Rutger J
AU  - Liu, Ruiqi
AU  - van der Made, Caspar I
AU  - van Rhijn, Norman
AU  - Groh, Laszlo
AU  - Klück, Viola
AU  - Janssen, Nico A F
AU  - Li, Wenchao
AU  - Rosati, Diletta
AU  - Alaswad, Ahmed
AU  - Tercan, Helin
AU  - Saiz, Jorge
AU  - Gonzalez-Riano, Carolina
AU  - van Uelft, Martina
AU  - Gaal, Orsolya Ildiko
AU  - Müller, Sophie
AU  - Ferreira, Humberto J
AU  - Warnat-Herresthal, Stefanie
AU  - Becker, Matthias
AU  - Holsten, Lisa
AU  - Kraut, Michael
AU  - Schulte-Schrepping, Jonas
AU  - Bonaguro, Lorenzo
AU  - Händler, Kristian
AU  - Cunha, Cristina
AU  - Schmolz, Manfred
AU  - Schultze, Joachim L
AU  - Joosten, Leo A B
AU  - Barbas, Coral
AU  - Netea, Mihai G
AU  - Li, Yang
AU  - Aschenbrenner, Anna C
AU  - Carvalho, Agostinho
AU  - van de Veerdonk, Frank L
TI  - Interferon gamma rebalances immunopathological signatures in chronic granulomatous disease through metabolic rewiring.
JO  - Blood advances
VL  - 9
IS  - 20
SN  - 2473-9529
CY  - Washington, DC
PB  - American Society of Hematology
M1  - DZNE-2025-01312
SP  - 5306 - 5322
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Granulomatous Disease, Chronic: metabolism
KW  - Granulomatous Disease, Chronic: immunology
KW  - Granulomatous Disease, Chronic: drug therapy
KW  - Granulomatous Disease, Chronic: pathology
KW  - Interferon-gamma: pharmacology
KW  - Interferon-gamma: therapeutic use
KW  - Reactive Oxygen Species: metabolism
KW  - Monocytes: metabolism
KW  - Monocytes: immunology
KW  - Monocytes: drug effects
KW  - Immunity, Innate: drug effects
KW  - NADPH Oxidases: metabolism
KW  - Male
KW  - Female
KW  - Interferon-gamma (NLM Chemicals)
KW  - Reactive Oxygen Species (NLM Chemicals)
KW  - NADPH Oxidases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40674716
C2  - pmc:PMC12556223
DO  - DOI:10.1182/bloodadvances.2025016213
UR  - https://pub.dzne.de/record/282549
ER  -