Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia

Nimitha R. Mathew, Janaki M. Vinnakota, Petya Apostolova, Daniel Erny, Shaimaa Hamarsheh, Geoffroy Andrieux, Jung Seok Kim, Kathrin Hanke, Tobias Goldmann, Louise Chappell-Maor, Nadia El-Khawanky, Gabriele Ihorst, Dominik Schmidt, Justus Duyster, Jürgen Finke, Thomas Blank, Melanie Boerries, Bruce R. Blazar, Steffen Jung, Marco PrinzRobert Zeiser

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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.

Original languageEnglish (US)
Pages (from-to)1315-1329
Number of pages15
JournalJournal of Clinical Investigation
Volume130
Issue number3
DOIs
StatePublished - Mar 2 2020

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Mathew, N. R., Vinnakota, J. M., Apostolova, P., Erny, D., Hamarsheh, S., Andrieux, G., Kim, J. S., Hanke, K., Goldmann, T., Chappell-Maor, L., El-Khawanky, N., Ihorst, G., Schmidt, D., Duyster, J., Finke, J., Blank, T., Boerries, M., Blazar, B. R., Jung, S., ... Zeiser, R. (2020). Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia. Journal of Clinical Investigation, 130(3), 1315-1329. https://doi.org/10.1172/JCI130272