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AhR activation mitigates graft-versus-host disease of the central nervous system by reducing microglial NF-κB signaling

Acute graft-versus-host disease (GVHD) that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) can affect the central nervous system (CNS). Most patients who have undergone allo-HCT receive antibiotic treatment, which alters the microbiome and essential microbiome-derived metaboli...

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Main Authors: Zähringer, Alexander Johannes (Author) , Morgado, Inês (Author) , Erny, Daniel (Author) , Ingelfinger, Florian (Author) , Gawron, Jana (Author) , Chatterjee, Sangya (Author) , Wenger, Valentin (Author) , Schmidt, Dominik (Author) , Schwöbel, Lennard (Author) , Adams, Rachael C. (Author) , Langenbach, Marlene (Author) , Hartmann, Alina (Author) , Osswald, Natascha (Author) , Wolf, Julian (Author) , Schlunck, Günther (Author) , Briquez, Priscilla S. (Author) , Grüter, Kathleen (Author) , Ruess, Dietrich A. (Author) , Frew, Ian (Author) , Burk, Ann-Cathrin (Author) , Holzmüller, Verena (Author) , Grimbacher, Bodo (Author) , Michonneau, David (Author) , Andrieux, Geoffroy (Author) , Socié, Gérard (Author) , Kolter, Julia (Author) , Boerries, Melanie (Author) , Follo, Marie (Author) , Blaeschke, Franziska (Author) , Sevenich, Lisa (Author) , Prinz, Marco (Author) , Zeiser, Robert (Author) , Vinnakota, Janaki Manoja (Author)
Format: Article (Journal)
Language:English
Published: June 24 2025
In: Blood advances
Year: 2025, Volume: 9, Issue: 12, Pages: 2935-2952
ISSN:2473-9537
DOI:10.1182/bloodadvances.2024015000
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1182/bloodadvances.2024015000
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Author Notes:Alexander Zähringer, Inês Morgado, Daniel Erny, Florian Ingelfinger, Jana Gawron, Sangya Chatterjee, Valentin Wenger, Dominik Schmidt, Lennard Schwöbel, Rachael C. Adams, Marlene Langenbach, Alina Hartmann, Natascha Osswald, Julian Wolf, Günther Schlunck, Priscilla S. Briquez, Kathleen Grueter, Dietrich A. Ruess, Ian Frew, Ann-Cathrin Burk, Verena Holzmüller, Bodo Grimbacher, David Michonneau, Geoffroy Andrieux, Gérard Socié, Julia Kolter, Melanie Boerries, Marie Follo, Franziska Blaeschke, Lisa Sevenich, Marco Prinz, Robert Zeiser, and Janaki Manoja Vinnakota
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Summary:Acute graft-versus-host disease (GVHD) that occurs after allogeneic hematopoietic cell transplantation (allo-HCT) can affect the central nervous system (CNS). Most patients who have undergone allo-HCT receive antibiotic treatment, which alters the microbiome and essential microbiome-derived metabolites. We investigated the impact of microbiome modifications on CNS GVHD and therapeutic strategies to overcome the microbiome-derived metabolite depletion. Antibiotic treatment of mice undergoing allo-HCT increased microglia numbers in the brain, indicating increased inflammation. In addition, microglial morphology shifted toward a highly branched phenotype. Consistent with a proinflammatory phenotype, the microglia exhibited increased NF-κB and Src activity. Antibiotic treatment caused the depletion of the bacteria-derived aryl hydrocarbon receptor (AhR) ligand indole-3-acetate in the brain. Conversely, treatment of the primary microglia with the AhR ligand 6-formylindolo(3,2-b)carbazole (FICZ) reduced NF-κB activity and phagocytic potential. Microglia expansion and morphological changes were reversed by AhR ligand FICZ treatment. Moreover, the AhR ligand indole-3-acetate was also reduced in the CNS of patients who developed acute GVHD concomitant with increased microglial NF-κB expression. In summary, we demonstrated that antibiotic treatment and a subsequent decrease of AhR ligands resulted in increased microglial activation in CNS GVHD. FICZ treatment hampered CNS inflammation by inhibiting NF-κB activity, thereby providing a metabolic modifier to interfere with pathogenic microglia signaling and CNS GVHD in vivo.
Item Description:Veröffentlicht: 12. Juni 2025
Gesehen am 06.11.2025
Physical Description:Online Resource
ISSN:2473-9537
DOI:10.1182/bloodadvances.2024015000

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