Home > Publications Database > Interferon gamma rebalances immunopathological signatures in chronic granulomatous disease through metabolic rewiring. > print

001     282549
005     20251218103441.0
024 7 _ |a 10.1182/bloodadvances.2025016213
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024 7 _ |a 2473-9529
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037 _ _ |a DZNE-2025-01312
041 _ _ |a English
082 _ _ |a 610
100 1 _ |a Bruno, Mariolina
|0 0000-0002-5353-7691
|b 0
245 _ _ |a Interferon gamma rebalances immunopathological signatures in chronic granulomatous disease through metabolic rewiring.
260 _ _ |a Washington, DC
|c 2025
|b American Society of Hematology
336 7 _ |a article
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336 7 _ |a ARTICLE
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520 _ _ |a 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.
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650 _ 7 |a Interferon-gamma
|0 82115-62-6
|2 NLM Chemicals
650 _ 7 |a Reactive Oxygen Species
|2 NLM Chemicals
650 _ 7 |a NADPH Oxidases
|0 EC 1.6.3.-
|2 NLM Chemicals
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Granulomatous Disease, Chronic: metabolism
|2 MeSH
650 _ 2 |a Granulomatous Disease, Chronic: immunology
|2 MeSH
650 _ 2 |a Granulomatous Disease, Chronic: drug therapy
|2 MeSH
650 _ 2 |a Granulomatous Disease, Chronic: pathology
|2 MeSH
650 _ 2 |a Interferon-gamma: pharmacology
|2 MeSH
650 _ 2 |a Interferon-gamma: therapeutic use
|2 MeSH
650 _ 2 |a Reactive Oxygen Species: metabolism
|2 MeSH
650 _ 2 |a Monocytes: metabolism
|2 MeSH
650 _ 2 |a Monocytes: immunology
|2 MeSH
650 _ 2 |a Monocytes: drug effects
|2 MeSH
650 _ 2 |a Immunity, Innate: drug effects
|2 MeSH
650 _ 2 |a NADPH Oxidases: metabolism
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Female
|2 MeSH
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700 1 _ |a Zhang, Bowen
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700 1 _ |a Röring, Rutger J
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700 1 _ |a van der Made, Caspar I
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700 1 _ |a van Rhijn, Norman
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700 1 _ |a Groh, Laszlo
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700 1 _ |a Müller, Sophie
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700 1 _ |a Händler, Kristian
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700 1 _ |a Cunha, Cristina
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700 1 _ |a Barbas, Coral
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700 1 _ |a Li, Yang
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700 1 _ |a van de Veerdonk, Frank L
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773 _ _ |a 10.1182/bloodadvances.2025016213
|g Vol. 9, no. 20, p. 5306 - 5322
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