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 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.

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Publication Details

Journal
Blood Advances
Published
2025-03-31
DOI
https://doi.org/10.1182/bloodadvances.2024015000
Citations
6
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
5.05
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article

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

Alina Hartmann, Lisa Sevenich, Ann‐Cathrin Burk, Gèrard Socié et al.
6 citations
Blood Advances
Neuroinflammation and Neurodegeneration Mechanisms
5.05
article

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

Alina Hartmann, Lisa Sevenich, Ann‐Cathrin Burk, Gèrard Socié, Marco Prinz, Verena Holzmüller, Janaki Manoja Vinnakota, Daniel Erny, Günther Schlunck, Julian Wolf, Dominik Schmidt, Jana Gawron, Melanie Börries, David Michonneau, Marie Follo, Dietrich Alexander Ruess, Priscilla S. Briquez, Franziska Blaeschke, Geoffroy Andrieux, Ian J. Frew, Bodo Grimbacher, Florian Ingelfinger, Julia Kolter, Marlene Langenbach, Rachael C. Adams, Inês Morgado, Robert Zeiser, Valentin Wenger, Alexander Zähringer, Subhendra Chatterjee, Natascha Oßwald, Kathleen Grueter, Lennard Frederik Schwöbel
article en
6 citations

Abstract

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.

Blood AdvancesVol. 9(12)
Inserm (FR), University of Freiburg (DE), The University of Queensland (AU), German Cancer Research Center (DE), Université Paris Cité (FR), QIMR Berghofer Medical Research Institute (AU), Heidelberg University (DE), University Medical Center Freiburg (DE), University Hospital Heidelberg (DE), Fred Hutch Cancer Center (US), Assistance Publique – Hôpitaux de Paris (FR), Hopp Children's Cancer Center Heidelberg (DE), Hôpitaux Universitaires Paris-Ouest (FR), Hertie Institute for Clinical Brain Research (DE), Hôpital Saint-Louis (FR), Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI) (DE), University of Tübingen (DE)
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Openalex Percentile: Top 5%
Neuroinflammation and Neurodegeneration Mechanisms
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