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Updated: Jan 1, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia
Nimitha R Mathew1,2, Janaki M Vinnakota1,2,3, Petya Apostolova1,2,4
1Department of Medicine I, Faculty of Medicine, Medical Center.
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.
Insights
Microglia play a key role in central nervous system (CNS) graft-versus-host disease (GVHD). Targeting the TAK1/TNF/MHC-II pathway in microglia offers a promising strategy to reduce neurotoxicity without affecting anti-leukemia effects.
Area of Science:
- Neuroimmunology
- Hematology
- Oncology
Background:
- Acute graft-versus-host disease (GVHD) can impact the central nervous system (CNS), but the role of microglia in this process is not well understood.
- Microglia, the resident immune cells of the brain, are implicated in neuroinflammation and neurological disorders.
Purpose of the Study:
- To elucidate the role of microglia in CNS GVHD.
- To identify molecular pathways mediating microglial activation and neurotoxicity in CNS GVHD.
- To evaluate the therapeutic potential of targeting microglia-derived factors in CNS GVHD.
Main Methods:
- Utilized mouse models of CNS GVHD with genetic deletion of TNF or TAK1 specifically in microglia.
- Performed RNA sequencing on purified microglia from GVHD mice.
- Assessed neuroinflammation, T cell infiltration, endothelial cell activation, and neurocognitive function.
- Investigated the effects of pharmacological TAK1 inhibition in vivo.
- Analyzed human CNS samples from GVHD patients.
Main Results:
- GVHD induction led to microglia activation, characterized by morphological changes and upregulation of MHC-II and CD80.
- Microglia from CNS GVHD mice showed increased TNF production.
- Selective deletion of TNF or TAK1 in microglia reduced MHC-II expression, CNS T cell infiltration, and endothelial cell activation.
- TAK1 activation in microglia was linked to NF-κB/p38 MAPK signaling.
- Pharmacological TAK1 inhibition improved neurocognitive activity and reduced GVHD-related pathology without compromising graft-versus-leukemia effects.
- Activated microglia with increased TNF production were observed in the CNS of human GVHD patients.
Conclusions:
- Microglia are key players in mediating CNS GVHD pathogenesis.
- The TAK1/TNF/MHC-II signaling axis in microglia is a critical mediator of CNS GVHD-induced neurotoxicity.
- Targeting microglial TAK1 presents a potential therapeutic strategy for mitigating CNS GVHD complications while preserving anti-leukemia immunity.
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