ROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
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Published:2024-01-10
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Maas-Bauer KristinaORCID, Stell Anna-VerenaORCID, Yan Kai-Li, de Vega Enrique, Vinnakota Janaki Manoja, Unger Susanne, Núñez Nicolas, Norona JohanaORCID, Talvard-Balland Nana, Koßmann Stefanie, Schwan Carsten, Miething CorneliusORCID, Martens Uta S., Shoumariyeh Khalid, Nestor Rosa P., Duquesne Sandra, Hanke Kathrin, Rackiewicz Michal, Hu ZehanORCID, El Khawanky Nadia, Taromi Sanaz, Andrlova Hana, Faraidun Hemin, Walter Stefanie, Pfeifer Dietmar, Follo Marie, Waldschmidt Johannes, Melchinger Wolfgang, Rassner Michael, Wehr ClaudiaORCID, Schmitt-Graeff Annette, Halbach SebastianORCID, Liao JamesORCID, Häcker Georg, Brummer TilmanORCID, Dengjel JoernORCID, Andrieux GeoffroyORCID, Grosse RobertORCID, Tugues Sonia, Blazar Bruce R.ORCID, Becher BurkhardORCID, Boerries MelanieORCID, Zeiser RobertORCID
Abstract
AbstractPatients 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.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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