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

doi:10.1038/nn.3531

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

Nat Neurosci. 2013 Nov;16(11):1618-26. doi: 10.1038/nn.3531. Epub 2013 Sep 29.

Authors

Tobias Goldmann¹, 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

Affiliation

¹ 1] Institute of Neuropathology, University of Freiburg, Freiburg, Germany. [2].

PMID: 24077561
DOI: 10.1038/nn.3531

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Newborn
Astrocytes / drug effects
Astrocytes / physiology
Brain / metabolism
Brain / pathology*
CD11c Antigen / genetics
CX3C Chemokine Receptor 1
Cells, Cultured
Disease Models, Animal
Dose-Response Relationship, Drug
Encephalomyelitis, Autoimmune, Experimental / chemically induced
Encephalomyelitis, Autoimmune, Experimental / pathology*
Estrogen Antagonists / pharmacology
Gene Expression Regulation / drug effects
Gene Expression Regulation / immunology*
Gene Targeting*
Luminescent Proteins / genetics
Lymph Nodes / pathology
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / metabolism*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microglia / drug effects
Microglia / physiology*
Nerve Tissue Proteins / metabolism
RNA, Untranslated / genetics
Receptors, Chemokine / genetics
Signal Transduction / drug effects
Signal Transduction / physiology
Tamoxifen / pharmacology

Substances

CD11c Antigen
CX3C Chemokine Receptor 1
Cx3cr1 protein, mouse
Estrogen Antagonists
Gt(ROSA)26Sor non-coding RNA, mouse
Luminescent Proteins
Nerve Tissue Proteins
RNA, Untranslated
Receptors, Chemokine
Tamoxifen
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7