학술논문
ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
Document Type
article
Author
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
Source
Nature Communications, Vol 15, Iss 1, Pp 1-18 (2024)
Subject
Language
English
ISSN
2041-1723
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.