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Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia
Nimitha R. Mathew, … , Marco Prinz, Robert Zeiser
Nimitha R. Mathew, … , Marco Prinz, Robert Zeiser
Published December 17, 2019
Citation Information: J Clin Invest. 2020;130(3):1315-1329. https://doi.org/10.1172/JCI130272.
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Research Article Article has an altmetric score of 18

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

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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.

Authors

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 Prinz, Robert Zeiser

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Figure 7

VCAM-1 and ICAM-1 expression after allo-HCT declines upon TAK1 inhibition.

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VCAM-1 and ICAM-1 expression after allo-HCT declines upon TAK1 inhibitio...
(A–D) Representative flow cytometry plots and the respective cumulative scatter plots showing quantification of the fold change of MFI of VCAM-1 (A and B) and ICAM-1 (C and D) expression in endothelial cells (CD31+CD105+) from the CNS of BALB/c mice treated with vehicle (n = 6) or takinib (n = 7) isolated on day 14 after allo-HCT. The experiment was performed once. (E–G) Immunofluorescence staining and scatter plots indicating the percentage of brain CD34+ endothelial cells expressing VCAM-1 and DAPI derived from BALB/c mice treated with vehicle (n = 7) or takinib (n = 7) (E) and from Tnffl/– (n = 7) or Cx3cr1creER Tnffl/– (n = 6) mice (F) on day 14 after allo-HCT. (G) Representative images from Tnffl/– and Cx3cr1creER Tnffl/– mice, respectively, are shown. Scale bars: 50 μm. The experiment was performed once. (H) Scatter plot showing the percentage of open-arm entries by mice treated with vehicle (n = 11), takinib (n = 12), or 5-Oz (n = 12) in an elevated plus maze test. (I) Scatter plot showing the percentage of time spent by mice treated with vehicle (n = 13), takinib (n = 12), or 5-Oz (n = 12) in exploring a novel object in a novel object recognition test. The experiments were performed 3 times, and the results (mean ± SEM) were pooled. (J) Survival rates of C57BL/6 mice with transplanted AML (FLT3-ITD/MLL-PTD) cells and BALB/c (WT) bone marrow (BM) along with (white and blue circles) and without (black circles) allogeneic T cells. (K) Survival rates of BALB/c mice with transplanted AML (WEHI-3B) cells and C57BL/6 BM (WT) along with (white and blue circles) and without (black circles) allogeneic T cells. The experiments were performed twice, and the results were pooled. P values were calculated using 2-sided Student’s unpaired t test (B, D, and F), Mann-Whitney U test (E), 1-way ANOVA (H and I), or 2-sided Mantel-Cox test (J and K).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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