Journal Article

DKFZ-2025-00687

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png AhR activation mitigates graft-versus-host disease of the central nervous system by reducing microglial NF-κB signaling.

Zähringer, A. ; Morgado, I. ; Erny, D. ; Ingelfinger, F. ; Gawron, J. ; Chatterjee, S. ; Wenger, V. ; Schmidt, D. ; Schwöbel, L. F. ; Adams, R. C. ; Langenbach, M. ; Hartmann, A. ; Osswald, N. ; Wolf, J. ; Schlunck, G. ; Briquez, P. S. ; Grüter, K.DKFZ* ; Ruess, D. A.DKFZ* ; Frew, I. ; Burk, A.-C.DKFZ* ; Holzmüller, V. ; Grimbacher, B. ; Michonneau, D. ; Andrieux, G. ; Socié, G. ; Kolter, J. ; Börries, M.DKFZ* ; Follo, M. ; Blaeschke, F.DKFZ* ; Sevenich, L. ; Prinz, M. ; Zeiser, R. ; Vinnakota, J. M.

2025
American Society of Hematology Washington, DC

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Please use a persistent id in citations: 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). The majority of allo-HCT patients 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, microglia morphology shifted towards a highly branched phenotype. Consistent with a pro-inflammatory phenotype microglia exhibited increased NF-κB and Src activity. Antibiotic treatment caused the depletion of the bacteria-derived arylhydrocarbon receptor (AhR) ligand indole-3-acetate in the brain. Conversely, treatment of 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 that 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 microglia activation during 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.

Note: 2025 Jun 24;9(12):2935-2952

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Contributing Institute(s):

1. NWG Pädriatische Immunonkologie (D270)
2. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 314 - Immunologie und Krebs (POF4-314) (POF4-314)

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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