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- Title
ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease.
- Authors
Maas-Bauer, Kristina; Stell, Anna-Verena; Yan, Kai-Li; de Vega, Enrique; Vinnakota, Janaki Manoja; Unger, Susanne; Núñez, Nicolas; Norona, Johana; Talvard-Balland, Nana; Koßmann, Stefanie; Schwan, Carsten; Miething, Cornelius; Martens, Uta S.; Shoumariyeh, Khalid; Nestor, Rosa P.; Duquesne, Sandra; Hanke, Kathrin; Rackiewicz, Michal; Hu, Zehan; El Khawanky, Nadia
- 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. Steroid-refractory acute graft-versus-host disease (aGVHD) is associated with a low one-year survival rate. Here, the authors show that ROCK1 is upregulated in leukocytes from patients with steroid-refractory aGVHD and that ROCK1/2 inhibition reduces the severity of aGVHD in mice by interfering with activation of multiple immune cell types.
- Subjects
GRAFT versus host disease; ACUTE diseases; MYELOID cells; DENDRITIC cells; SURVIVAL rate; CELL migration inhibition; T cells
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-024-44703-7