ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease.

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 15 Issue 1 Pg. 446 (Jan 10 2024) ISSN: 2041-1723 [Electronic] England
• PMID: 38199985 (Publication Type: Journal Article)
• Copyright: © 2024. The Author(s).

Chemical References

• rho-Associated Kinases
• NF-kappa B
• Adrenal Cortex Hormones
• ROCK1 protein, human

Topics

• Humans
• Animals
• Mice
• rho-Associated Kinases (genetics)
• Graft vs Host Disease (drug therapy)
• Signal Transduction
• NF-kappa B
• Adrenal Cortex Hormones (pharmacology, therapeutic use)