Academic Journal
ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
| العنوان: | ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease |
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| المؤلفون: | 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, Taromi, Sanaz, Andrlova, Hana, Faraidun, Hemin, Walter, Stefanie, Pfeifer, Dietmar, Follo, Marie, Waldschmidt, Johannes, Melchinger, Wolfgang, Rassner, Michael, Wehr, Claudia, Schmitt-Graeff, Annette, Halbach, Sebastian, Liao, James, Häcker, Georg, Brummer, Tilman, Dengjel, Joern, Andrieux, Geoffroy, Grosse, Robert, Tugues, Sonia, Blazar, Bruce R., Becher, Burkhard, Boerries, Melanie, Zeiser, Robert |
| المصدر: | Nature Communications ; volume 15, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2024 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-024-44703-7 |
| الاتاحة: | http://dx.doi.org/10.1038/s41467-024-44703-7 https://www.nature.com/articles/s41467-024-44703-7.pdf https://www.nature.com/articles/s41467-024-44703-7 |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.AB319EF7 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-024-44703-7 |
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