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

Blood Adv. 2025 Jun 24;9(12):2935-2952. doi: 10.1182/bloodadvances.2024015000.

Alexander Zähringer ¹, Inês Morgado ¹ ², Daniel Erny ³, Florian Ingelfinger ¹, Jana Gawron ¹ ², Sangya Chatterjee ¹ ², Valentin Wenger ¹, Dominik Schmidt ¹ ², Lennard Schwöbel ¹, Rachael C Adams ⁴ ⁵ ⁶, Marlene Langenbach ¹ ², Alina Hartmann ¹, Natascha Osswald ¹, Julian Wolf ⁷, Günther Schlunck ⁷, Priscilla S Briquez ⁸ ⁹ ¹⁰, Kathleen Grueter ¹¹ ¹² ¹³, Dietrich A Ruess ⁸ ¹⁴, Ian Frew ¹, Ann-Cathrin Burk ¹ ² ¹⁴, Verena Holzmüller ¹ ² ⁹, Bodo Grimbacher ¹⁵, David Michonneau ¹⁶ ¹⁷ ¹⁸, Geoffroy Andrieux ¹⁹, Gérard Socié ¹⁶ ¹⁷ ¹⁸, Julia Kolter ¹⁵ ²⁰, Melanie Boerries ¹⁰ ¹³, Marie Follo ¹, Franziska Blaeschke ¹¹ ¹² ²¹, Lisa Sevenich ²² ²³, Marco Prinz ³ ¹⁰, Robert Zeiser ¹ ¹⁰, Janaki Manoja Vinnakota ¹

Affiliations

1 Department of Medicine I, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
2 Faculty of Biology, University of Freiburg, Freiburg, Germany.
3 Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
4 Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
5 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
6 Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA.
7 Department of Ophthalmology, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
8 Department of General and Visceral Surgery, Center for Surgery, Medical Center University of Freiburg, Freiburg, Germany.
9 Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany.
10 Signaling Research Centers BIOSS and CIBSS, Center for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
11 German Cancer Research Center (DKFZ), Heidelberg, Germany.
12 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg University Hospital, Heidelberg, Germany.
13 Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
14 German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between DKFZ and Medical Center University of Freiburg, Freiburg, Germany.
15 Center for Chronic Immunodeficiency CCI, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
16 Department of Hematology, Hôpitaux Universitaires Saint-Louis, Paris, France.
17 Hematology and Transplantation Unit, Saint-Louis Hospital, APHP, Paris, France.
18 INSERM UMR1342 Saint-Louis Research Institute, Team Translational Immunology in Immunotherapies and Hematology, IHU Leukemia Institute Paris Saint-Louis, Paris Cité University, Paris, France.
19 Institute of Medical Bioinformatics and Systems Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
20 Institute for Infection Prevention and Control, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
21 Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital (UKHD), Heidelberg, Germany.
22 Department of Neurology and Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research (HIH) and M3 Research Center, University Hospital Tübingen, Tübingen, Germany.
23 Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.

PMID: 40163754 DOI: 10.1182/bloodadvances.2024015000

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-12451

FICZ

99.42%, AhR Agonist

Aryl Hydrocarbon Receptor

Others

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