Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia
| Autor: | Shaima’a Hamarsheh, Kathrin Hanke, Melanie Boerries, Jung-Seok Kim, Justus Duyster, Nimitha R. Mathew, Steffen Jung, Nadia El-Khawanky, Dominik Schmidt, Thomas Blank, Louise Chappell-Maor, Tobias Goldmann, Jürgen Finke, Daniel Erny, Gabriele Ihorst, Marco Prinz, Petya Apostolova, Janaki Manoja Vinnakota, Bruce R. Blazar, Geoffroy Andrieux, Robert Zeiser |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
T cell CX3C Chemokine Receptor 1 Graft vs Host Disease Vascular Cell Adhesion Molecule-1 chemical and pharmacologic phenomena 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Central Nervous System Diseases Medicine Animals Humans Mice Knockout Mice Inbred BALB C Microglia business.industry Tumor Necrosis Factor-alpha Neurotoxicity Histocompatibility Antigens Class II General Medicine Th1 Cells medicine.disease MAP Kinase Kinase Kinases Up-Regulation Transplantation Disease Models Animal 030104 developmental biology medicine.anatomical_structure Graft-versus-host disease surgical procedures operative 030220 oncology & carcinogenesis Acute Disease Cancer research Th17 Cells Tumor necrosis factor alpha business CD80 Research Article |
| Zdroj: | J Clin Invest Journal of Clinical Investigation |
| ISSN: | 1558-8238 |
| Popis: | 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 Cx3cr1(creER) Tnf(fl/–) 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 Cx3cr1(creER) Tak1(fl/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. |
| Databáze: | OpenAIRE |
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