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30 de julio de 2025
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Interferon gamma rebalances immunopathological signatures in Chronic Granulomatous Disease through metabolic rewiring.

Publicado en:Blood Advances. bloodadvances.2025016213-bloodadvances.2025016213 - 2025-07-17 (), DOI: 10.1182/bloodadvances.2025016213

Autores: Bruno M; Kröger C; Ferreira AV; Zhang B; Röring RJ; Liu R; van der Made CI; van Rhijn N; Groh L; Klück V; Janssen NAF; Li W; Rosati D; Alaswad A; Tercan H; Saiz J; Gonzalez-Riano C; Uelft MV; Gaal O; Müller S; Ferreira HJ; Warnat-Herresthal S; Becker M; Holsten L; Kraut M; Schulte-Schrepping J; Bonaguro L; Händler K; Cunha C; Schmolz M; Schultze JL; Joosten L; Barbas C; Netea MG; Li Y; Aschenbrenner AC; Carvalho A; van de Veerdonk FL

Afiliaciones

Centre for Metabolomics and Bioanalysis (CEMBIO), Chemistry and Biochemistry Department, Pharmacy Faculty, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain. - Autor o Coautor
Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. - Autor o Coautor
Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), a joint venture between the Hannover Medical School (MHH) and the Helmholtz Cent, Hannover, Germany. - Autor o Coautor
Department of Computational Biology for Individualised Medicine, Centre for Individualised Infection Medicine (CiiM), Hannover, Germany. - Autor o Coautor
Department of Internal Medicine and Radboudumc Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands. - Autor o Coautor
Department of Medical Genetics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania. - Autor o Coautor
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Bonn, Germany. - Autor o Coautor
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany. - Autor o Coautor
Deutsches Zentrum für Neurodegenerative Erkrankungen, DZNE, Bonn, Germany. - Autor o Coautor
DZNE, Bonn, Germany. - Autor o Coautor
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. - Autor o Coautor
HOT Screen GmbH, Reutlingen, Germany. - Autor o Coautor
Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. - Autor o Coautor
Life and Medical Sciences Institute, University of Bonn, Bonn, Germany. - Autor o Coautor
Microbial Evolution Research Manchester, Division of Evolution, Infection and Genomic Sciences, Faculty of Medicine, Biology and Health, University of Manchester,, Manchester, United Kingdom. - Autor o Coautor
Murdoch Children's Research Institute, Parkville, Australia. - Autor o Coautor
PRECISE Platform for Single Cell Genomics and Epigenomics, DZNE and University of Bonn, Bonn, Germany. - Autor o Coautor
Radboud University Medical Center, Nijmegen, Netherlands. - Autor o Coautor
Radboud University Nijmegen Medical Centre, Cambridge, Massachusetts, United States. - Autor o Coautor
Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Bonn, Germany. - Autor o Coautor
Universidad CEU San Pablo CEMBIO, Madrid, Spain. - Autor o Coautor
Universitätsklinikum Schleswig-Holstein (UKSH), University of Lübeck and University of Kiel, Lübeck, Germany. - Autor o Coautor
University of Minho, Braga, Portugal. - Autor o Coautor
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Resumen

Chronic granulomatous disease (CGD) is a primary immunodeficiency 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 (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 show that innate immune cells of CGD patients 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 acids concentrations and profound functional metabolic defects, both at the level of glycolysis and mitochondrial respiration. Ex vivo and in vivo treatment with IFN-γ restored these metabolic defects and reduced excessive 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.

Palabras clave

Hematology

Indicios de calidad

Impacto bibliométrico. Análisis de la aportación y canal de difusión

El trabajo ha sido publicado en la revista Blood Advances debido a la progresión y el buen impacto que ha alcanzado en los últimos años, según la agencia WoS (JCR), se ha convertido en una referencia en su campo. En el año de publicación del trabajo, 2025, se encontraba en la posición 13/98, consiguiendo con ello situarse como revista Q1 (Primer Cuartil), en la categoría Hematology.