Nature Communications (Jan 2024)
ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
- Kristina Maas-Bauer,
- Anna-Verena Stell,
- Kai-Li Yan,
- Enrique de Vega,
- Janaki Manoja Vinnakota,
- Susanne Unger,
- Nicolas Núñez,
- Johana Norona,
- Nana Talvard-Balland,
- Stefanie Koßmann,
- Carsten Schwan,
- Cornelius Miething,
- Uta S. Martens,
- Khalid Shoumariyeh,
- Rosa P. Nestor,
- Sandra Duquesne,
- Kathrin Hanke,
- Michal Rackiewicz,
- Zehan Hu,
- Nadia El Khawanky,
- Sanaz Taromi,
- Hana Andrlova,
- Hemin Faraidun,
- Stefanie Walter,
- Dietmar Pfeifer,
- Marie Follo,
- Johannes Waldschmidt,
- Wolfgang Melchinger,
- Michael Rassner,
- Claudia Wehr,
- Annette Schmitt-Graeff,
- Sebastian Halbach,
- James Liao,
- Georg Häcker,
- Tilman Brummer,
- Joern Dengjel,
- Geoffroy Andrieux,
- Robert Grosse,
- Sonia Tugues,
- Bruce R. Blazar,
- Burkhard Becher,
- Melanie Boerries,
- Robert Zeiser
Affiliations
- Kristina Maas-Bauer
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Anna-Verena Stell
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Kai-Li Yan
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Enrique de Vega
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Janaki Manoja Vinnakota
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Susanne Unger
- Institute of Experimental Immunology, University of Zurich
- Nicolas Núñez
- Institute of Experimental Immunology, University of Zurich
- Johana Norona
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Nana Talvard-Balland
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Stefanie Koßmann
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Carsten Schwan
- Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg
- Cornelius Miething
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Uta S. Martens
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Khalid Shoumariyeh
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Rosa P. Nestor
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Sandra Duquesne
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Kathrin Hanke
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Michal Rackiewicz
- Department of Biology, University of Fribourg
- Zehan Hu
- Department of Biology, University of Fribourg
- Nadia El Khawanky
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Sanaz Taromi
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Hana Andrlova
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Hemin Faraidun
- Faculty of Biology, University of Freiburg
- Stefanie Walter
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Dietmar Pfeifer
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Marie Follo
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Johannes Waldschmidt
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Wolfgang Melchinger
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Michael Rassner
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Claudia Wehr
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- Annette Schmitt-Graeff
- Institute of Pathology, University Hospital Freiburg
- Sebastian Halbach
- German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg
- James Liao
- Department of Medicine, University of Arizona
- Georg Häcker
- IMMH, University Hospital Freiburg, Faculty of Medicine
- Tilman Brummer
- German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg
- Joern Dengjel
- Department of Biology, University of Fribourg
- Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg
- Robert Grosse
- Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg
- Sonia Tugues
- Institute of Experimental Immunology, University of Zurich
- Bruce R. Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota
- Burkhard Becher
- Institute of Experimental Immunology, University of Zurich
- Melanie Boerries
- German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg
- Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg
- DOI
- https://doi.org/10.1038/s41467-024-44703-7
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 18
Abstract
Abstract Patients with corticosteroid-refractory acute graft-versus-host disease (aGVHD) have a low one-year survival rate. Identification and validation of novel targetable kinases in patients who experience corticosteroid-refractory-aGVHD may help improve outcomes. Kinase-specific proteomics of leukocytes from patients with corticosteroid-refractory-GVHD identified rho kinase type 1 (ROCK1) as the most significantly upregulated kinase. ROCK1/2 inhibition improved survival and histological GVHD severity in mice and was synergistic with JAK1/2 inhibition, without compromising graft-versus-leukemia-effects. ROCK1/2-inhibition in macrophages or dendritic cells prior to transfer reduced GVHD severity. Mechanistically, ROCK1/2 inhibition or ROCK1 knockdown interfered with CD80, CD86, MHC-II expression and IL-6, IL-1β, iNOS and TNF production in myeloid cells. This was accompanied by impaired T cell activation by dendritic cells and inhibition of cytoskeletal rearrangements, thereby reducing macrophage and DC migration. NF-κB signaling was reduced in myeloid cells following ROCK1/2 inhibition. In conclusion, ROCK1/2 inhibition interferes with immune activation at multiple levels and reduces acute GVHD while maintaining GVL-effects, including in corticosteroid-refractory settings.
