Journal Article

DZNE-2025-01312

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Interferon gamma rebalances immunopathological signatures in chronic granulomatous disease through metabolic rewiring.

Bruno, M. ; Kröger, C.DZNE* ; 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.DZNE* ; Gaal, O. I. ; Müller, S.DZNE* ; Ferreira, H. J.DZNE* ; Warnat-Herresthal, S.DZNE* ; Becker, M.DZNE* ; Holsten, L.DZNE* ; Kraut, M.DZNE* ; Schulte-Schrepping, J.DZNE* ; Bonaguro, L.DZNE* ; Händler, K.DZNE* ; Cunha, C. ; Schmolz, M. ; Schultze, J. L.DZNE* ; Joosten, L. A. B.DZNE* ; Barbas, C. ; Netea, M. G. ; Li, Y. ; Aschenbrenner, A. C.DZNE* ; Carvalho, A. ; van de Veerdonk, F. L.

2025
American Society of Hematology Washington, DC

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Please use a persistent id in citations: doi:10.1182/bloodadvances.2025016213

Abstract: 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.

Keyword(s): Humans (MeSH) ; Granulomatous Disease, Chronic: metabolism (MeSH) ; Granulomatous Disease, Chronic: immunology (MeSH) ; Granulomatous Disease, Chronic: drug therapy (MeSH) ; Granulomatous Disease, Chronic: pathology (MeSH) ; Interferon-gamma: pharmacology (MeSH) ; Interferon-gamma: therapeutic use (MeSH) ; Reactive Oxygen Species: metabolism (MeSH) ; Monocytes: metabolism (MeSH) ; Monocytes: immunology (MeSH) ; Monocytes: drug effects (MeSH) ; Immunity, Innate: drug effects (MeSH) ; NADPH Oxidases: metabolism (MeSH) ; Male (MeSH) ; Female (MeSH) ; Interferon-gamma ; Reactive Oxygen Species ; NADPH Oxidases

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Contributing Institute(s):

1. Aging and Immunity (AG Aschenbrenner)
2. Clinical Single Cell Omics (CSCO) / Systems Medicine (AG Schultze)
3. Molecular and Translational Immunaging (AG Bonaguro)
4. Modular High Performance Computing and Artificial Intelligence (AG Becker)
5. Platform for Single Cell Genomics and Epigenomics (PRECISE)

Research Program(s):

1. 354 - Disease Prevention and Healthy Aging (POF4-354) (POF4-354)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Experiment(s):

1. Platform for Single Cell Genomics and Epigenomics at DZNE University of Bonn

Appears in the scientific report 2025

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Database coverage:
; ; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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