Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia.
R Mathew N, Vinnakota JM, Apostolova P, Erny D, Hamarsheh S, Andrieux G, Kim JS, Hanke K, Goldmann T, Chappell-Maor L, El-Khawanky N, Ihorst G, Schmidt D, Duyster J, Finke J, Blank T, Boerries M, Blazar BR, Jung S, Prinz M, Zeiser R.
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, MHC-II- and CD80-upregulation occurred upon GVHD induction. RNA-sequencing-based analysis of purified microglial obtained from mice with CNS-GVHD revealed TNF upregulation. Selective TNF gene deletion in microglia of Cx3cr1creER:Tnffl/-mice reduced MHC-II-expression, 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, microglial MHC-II, and improved neurocognitive-activity. In summary, we prove a role for microglia in CNS-GVHD, identify the TAK1/TNF/MHC-II axis as mediator of CNS-GVHD and provide a novel TAK1 inhibitor-based approach against GVHD-induced neurotoxicity.
