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

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
10 Jan 2024
Historique:
received: 18 04 2020
accepted: 20 12 2023
medline: 11 1 2024
pubmed: 11 1 2024
entrez: 10 1 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-44703-7 PMID: 38199985
pubmed: 38199985
doi: 10.1038/s41467-024-44703-7
pii: 10.1038/s41467-024-44703-7
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

446

Subventions

Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : SFB-1479 - Project ID: 441891347SFB1160
Organisme : Deutsche Forschungsgemeinschaft (German Research Foundation)
ID : Project ID 431984000 - CRC1453 - S1 to M.B
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : EU Proposal n° ERC-2022-ADG Project: 101094168 - AlloCure (ERC Advanced grant to R.Z.)
Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)
ID : R01 HL56067; R37 AI34495 (NIH fund to B.R.B.)

Informations de copyright

© 2024. The Author(s).

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Auteurs

Kristina Maas-Bauer (K)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0003-1788-2807

Anna-Verena Stell (AV)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
ORCID: 0009-0002-5352-4871

Kai-Li Yan (KL)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Enrique de Vega (E)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany.

Janaki Manoja Vinnakota (JM)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Susanne Unger (S)

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Nicolas Núñez (N)

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Johana Norona (J)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0002-6675-322X

Nana Talvard-Balland (N)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Stefanie Koßmann (S)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Carsten Schwan (C)

Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, Freiburg, Germany.

Cornelius Miething (C)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0003-4699-3805

Uta S Martens (US)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, Freiburg, Germany.

Khalid Shoumariyeh (K)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg, Freiburg, Germany.

Rosa P Nestor (RP)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Sandra Duquesne (S)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Kathrin Hanke (K)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Michal Rackiewicz (M)

Department of Biology, University of Fribourg, Fribourg, Switzerland.
Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.

Zehan Hu (Z)

Department of Biology, University of Fribourg, Fribourg, Switzerland.
Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0001-6182-4781

Nadia El Khawanky (N)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Sanaz Taromi (S)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Hana Andrlova (H)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Hemin Faraidun (H)

Faculty of Biology, University of Freiburg, Freiburg, Germany.

Stefanie Walter (S)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Dietmar Pfeifer (D)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Marie Follo (M)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Johannes Waldschmidt (J)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Wolfgang Melchinger (W)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Michael Rassner (M)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Claudia Wehr (C)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0002-5037-6175

Annette Schmitt-Graeff (A)

Institute of Pathology, University Hospital Freiburg, Freiburg, Germany.

Sebastian Halbach (S)

German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg, Freiburg, Germany.
IMMZ, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
ORCID: 0000-0002-6827-8178

James Liao (J)

Department of Medicine, University of Arizona, Tucson, USA.
ORCID: 0000-0001-9679-4252

Georg Häcker (G)

IMMH, University Hospital Freiburg, Faculty of Medicine, Freiburg, Germany.

Tilman Brummer (T)

German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg, Freiburg, Germany.
IMMZ, University of Freiburg, Faculty of Medicine, Freiburg, Germany.
Signaling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0003-4387-7905

Joern Dengjel (J)

Department of Biology, University of Fribourg, Fribourg, Switzerland.
Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0002-9453-4614

Geoffroy Andrieux (G)

Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0002-5389-9481

Robert Grosse (R)

Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty, University of Freiburg, Freiburg, Germany.
CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0002-3380-5273

Sonia Tugues (S)

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Bruce R Blazar (BR)

Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN, USA.
ORCID: 0000-0002-9608-9841

Burkhard Becher (B)

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
ORCID: 0000-0002-1541-7867

Melanie Boerries (M)

German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg, Freiburg, Germany.
Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
ORCID: 0000-0002-3670-0602

Robert Zeiser (R)

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.
German Cancer Consortium (DKTK), Partner Site Freiburg, a partnership between German Cancer Research Center (DKFZ) and Medical Center - University of Freiburg, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.
Signaling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany. robert.zeiser@uniklinik-freiburg.de.
ORCID: 0000-0001-6565-3393

Classifications MeSH