A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation

Tobias Goldmann, Peter Wieghofer, Philippe F. Müller, Yochai Wolf, Diana Varol, Simon Yona, Stefanie M. Brendecke, Katrin Kierdorf, Ori Staszewski, Moumita Datta, Tom Luedde, Mathias Heikenwalder, Steffen Jung, Marco Prinz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Microglia are brain macrophages and, as such, key immune-competent cells that can respond to environmental changes. Understanding the mechanisms of microglia-specific responses during pathologies is hence vital for reducing disease burden. The definition of microglial functions has so far been hampered by the lack of genetic in vivo approaches that allow discrimination of microglia from closely related peripheral macrophage populations in the body. Here we introduce a mouse experimental system that specifically targets microglia to examine the role of a mitogen-associated protein kinase kinase kinase (MAP3K), transforming growth factor (TGF)-β-activated kinase 1 (TAK1), during autoimmune inflammation. Conditional depletion of TAK1 in microglia only, not in neuroectodermal cells, suppressed disease, significantly reduced CNS inflammation and diminished axonal and myelin damage by cell-autonomous inhibition of the NF-κB, JNK and ERK1/2 pathways. Thus, we found TAK1 to be pivotal in CNS autoimmunity, and we present a tool for future investigations of microglial function in the CNS.

Original languageEnglish
Pages (from-to)1618-1626
Number of pages9
JournalNature Neuroscience
Volume16
Issue number11
DOIs
StatePublished - Nov 2013
Externally publishedYes

Funding

FundersFunder number
Fritz-Thyssen Foundation
GHSTSFB620
Gemeinnützige Hertie Foundation
Helmholtz FoundationSFB-TR36
European Research Council
Deutsche ForschungsgemeinschaftPR 577/8-1, FOR1336, SFB 992
Bundesministerium für Bildung und Forschung
Israel Science Foundation
Helmholtz Alliance for Astroparticle Physics

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