1. Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia
- Author
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Mathew, Nimitha R., Vinnakota, Janaki M., Apostolova, Petya, Erny, Daniel, Hamarsheh, Shaimaa, Andrieux, Geoffroy, Kim, Jung-Seok, Hanke, Kathrin, Goldmann, Tobias, Chappell-Maor, Louise, Khawanky, Nadia El-, Ihors, Gabriele, Schmid, Dominik, Duyster, Justus, Finke, Jurgen, Blank, Thomas, Boerries, Melanie, Blazar, Bruce R., Jung, Steffen, Prinz, Marco, and Zeiser, Robert
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Tumor necrosis factor -- Analysis ,Transforming growth factors -- Analysis ,Bone morphogenetic proteins -- Analysis ,RNA sequencing -- Analysis ,T cells -- Analysis ,Genes ,Endothelium ,Leukemia ,RNA ,Central nervous system ,Diseases ,Health care industry - 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 [Cx3cr1.sup.creER] [Tnf.sup.fl-] mice reduced MHC-II expression and decreased CNS T cell infiltrates and [VCAM-1.sup.+] endothelial cells. GVHD increased microglia TGF-[beta]-activated kinase-1 (TAK1) activation and NF-[kappa]B/p38 MAPK signaling. Selective Tak1 deletion in microglia using [Cx3cr1.sup.creER] [Tak1.sup.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.sup.+] 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., Introduction Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). About 50% of patients with severe acute GVHD fail to respond to corticosteroids, and steroid-refractory [...]
- Published
- 2020
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