@article{5df2b555e72f4b0380b69d542bc030bf,
title = "Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia",
abstract = "Acute graft-versus-host disease (GVHD) can affect the central nervous system (CNS). The role of microglia in CNS-GVHD remains undefined. In agreement with microglia activation, we found that profound morphological changes and MHC-II and CD80 upregulation occurred upon GVHD induction. RNA sequencing-based analysis of purified microglia obtained from mice with CNS-GVHD revealed TNF upregulation. Selective TNF gene deletion in microglia of Cx3cr1creER Tnffl/- mice reduced MHC-II expression and decreased CNS T cell infiltrates and VCAM-1+ endothelial cells. GVHD increased microglia TGF-β-activated kinase-1 (TAK1) activation and NF-κB/p38 MAPK signaling. Selective Tak1 deletion in microglia using Cx3cr1creER Tak1fl/fl mice resulted in reduced TNF production and microglial MHC-II and improved neurocognitive activity. Pharmacological TAK1 inhibition reduced TNF production and MHC-II expression by microglia, Th1 and Th17 T cell infiltrates, and VCAM-1+ endothelial cells and improved neurocognitive activity, without blocking graft-versus-leukemia effects. Consistent with these findings in mice, we observed increased activation and TNF production of microglia in the CNS of GVHD patients. In summary, we prove a role for microglia in CNS-GVHD, identify the TAK1/TNF/MHC-II axis as a mediator of CNS-GVHD, and provide a TAK1 inhibitor-based approach against GVHD-induced neurotoxicity.",
author = "Mathew, {Nimitha R} and Vinnakota, {Janaki M} and Petya Apostolova and Daniel Erny and Shaimaa Hamarsheh and Geoffroy Andrieux and Jung-Seok Kim and Kathrin Hanke and Tobias Goldmann and Louise Chappell-Maor and Nadia El-Khawanky and Gabriele Ihorst and Dominik Schmidt and Justus Duyster and J{\"u}rgen Finke and Thomas Blank and Melanie Boerries and Blazar, {Bruce R} and Steffen Jung and Marco Prinz and Robert Zeiser",
note = "We thank Eileen Barleon for performing immunohistochemistry, Klaus Geiger and Dieter Herchenbach for cell sorting, Heide Dierbach and Katja Graewe for tissue processing and staining, Britta Fritsch and Mate Dobrossy for providing the grip strength meter and elevated plus maze, respectively, Omar Mossad for his help with RNA isolation and endothelial isolation, and Takahiro Masuda for the inducible Cre-reporter line leakiness analysis. We acknowledge the team of the Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany, for their sequencing service. This study was supported by Deutsche Forschungsgemeinschaft (DFG) grants SFB TRR167 (to RZ, DE, TB, SJ, and MP), SFB1160 TP B09 (to RZ), and SFB 850 (to MB) and DFG individual grant 872/4-1 (to RZ); the European Union{\textquoteright}s GVHDCure (ERC consolidator grant to RZ); Deutsche Krebshilfe (70113473); the Jos{\'e} Carreras Leukaemia Foundation (DJCLS 01R/2019 to RZ); Germany{\textquoteright}s Excellence Strategy (Centre for Integrative Biological Signalling Studies, EXC-2189, Project ID 390939984 to RZ); and the Interreg V European Regional Development Fund (European Union) program (project 3.2 TRIDIAG to RZ). PA was supported by the Else Kr{\"o}ner-Fresenius-Stiftung (EKFS 2015_A147). PA and DE are supported by the Berta-Ottenstein-Programme for Clinician Scientists. MB is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (coNfirm, FKZ 01ZX1708F) and within the Medical Informatics Funding Scheme (MIRACUM, FKZ 01ZZ1606A-H). Author Contributions: NRM and JMV performed the majority of the murine and cell line experiments and helped to develop the overall concept and write the manuscript. NRM and JMV are co–first authors. Their order in the author list was based on the first key experiments, which were performed and analyzed by NRM. PA, DE, and GI collected and analyzed patient samples. JSK performed cell sorting. SH, KH, NEK, DS, and TG helped with in vivo experiments. GA, MB, and LCM performed RNA sequencing and analyzed the data. TB helped to develop the concept and provided help with behavioral studies in mice. JD, JF, BRB, SJ, and MP contributed to critical analysis of the data, developed concepts, and provided reagents. RZ developed the overall concept, supervised the experiments, analyzed data, and wrote the manuscript.",
year = "2020",
month = mar,
day = "2",
doi = "https://doi.org/10.1172/JCI130272",
language = "الإنجليزيّة",
volume = "130",
pages = "1315--1329",
journal = "The Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "3",
}