CoChat
Sign Up
Cited by 688Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesNF-κB Signaling Pathways

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

Goldmann, Tobias, Wieghofer, Peter, Müller, Philippe F, Wolf, Yochai, Varol, Diana, Yona, Simon, Brendecke, Stefanie M, Kierdorf, Katrin +6 more·2013·Nature Neuroscience
DOI 10.1038/nn.3531
Open this paper in CoChat — free account

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.

Integrity signals

Registry

Crossref · 10.1038/nn.3531

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • After tamoxifen withdrawal, short-lived Ai6-ZsGreen-expressing cells in the periphery are promptly replaced by newly derived cells lacking Ai6-ZsGreen expression, whereas the long-lived nature of microglia allows them to retain their Ai6-ZsGreen signal for months post-tamoxifen withdrawal.

    “Following the withdrawal of tamoxifen, short-lived Ai6-ZsGreen expressing cells in the periphery are promptly replaced by newly derived cells that lack Ai6-ZsGreen expression.”

    From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Goldmann et al., 2013

  • Genetic ablation of TAK1 in long-lived CX3CR1+ cells attenuated EAE pathology, associated with reduced cellular infiltration into the CNS, reduced myelin destruction and axonal loss, and suppression of proinflammatory genes.

    “Genetic ablation of TAK1 in long-lived CX3CR1+ cells attenuated EAE pathology [129]. This was associated with reduced cellular infiltration into the CNS, reduced myelin destruction and axonal loss, and suppression of proinflammatory genes.”

    From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [129]

  • This study supports the pathogenic role of microglia in EAE via the production of inflammatory mediators.

    “Using a more targeted approach to study microglia, this study supports the pathogenic role of these cells in EAE via the production of inflammatory mediators.”

    From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [129]

  • The majority of peripheral immune cells that express Cx3cr1 are short lived and turn over within 4 weeks because of ongoing, lifelong hematopoiesis.

    “However, the majority of these peripheral cells are short lived and turn over within 4 weeks because of ongoing, lifelong hematopoiesis.10–12”

    From A comparative analysis of microglial inducible Cre lines (2023) · cites this paper as [12]

  • Microglia are highly heterogeneous throughout the brain, especially during the early postnatal period.

    “It is known that, especially during the early postnatal period, microglia are highly heterogeneous throughout the brain16.”

    From Constitutive expression of CX3CR1-BAC-Cre introduces minimal off-target effects in microglia (2026) · cites this paper as [16]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Goldmann, T., Wieghofer, P., Müller, P. F., Wolf, Y., Varol, D., Yona, S., Brendecke, S. M., Kierdorf, K., Staszewski, O., Datta, M., Luedde, T., Heikenwalder, M., Jung, S., & Prinz, M.
Affiliations
  • University of Freiburg (DE)
  • Weizmann Institute of Science (IL)
  • RWTH Aachen University (DE)
Corresponding author
  • Jung, Steffen
  • Prinz, Marco
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2013-09-29
Volume
16
Issue
11
Pages
1618-1626
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.3531
OpenAlex
W2019604999
Cited by
688
References
55
Citations by year
2026: 28 · 2025: 36 · 2024: 61 · 2023: 66 · 2022: 61 · 2021: 67 · 2020: 56 · 2019: 57 · 2018: 61 · 2017: 48 · 2016: 57 · 2015: 59 · 2014: 29 · 2013: 1
FWCI
27.25
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
  • Site cant be reached (submittedVersion)
  • RWTH Publications (RWTH Aachen) (submittedVersion)
  • OPUS (Augsburg University) (submittedVersion)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
microglia, TAK1, conditional gene targeting, multiple sclerosis, central nervous system autoimmunity, neuroinflammation, NF-κB signaling, JNK signaling, ERK signaling, MAP3K, myelin damage, axonal injury
MeSH terms
CX3C Chemokine Receptor 1, MAP Kinase Kinase Kinase 7, Animals, Animals, Newborn, Astrocytes, Brain, Cells, Cultured, Disease Models, Animal, Dose-Response Relationship, Drug, Encephalomyelitis, Autoimmune, Experimental, Estrogen Antagonists, Gene Expression Regulation, Luminescent Proteins, Lymph Nodes, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins, Tamoxifen, Signal Transduction, Microglia, Gene Targeting, Receptors, Chemokine, MAP Kinase Kinase Kinases, RNA, Untranslated, CD11c Antigen, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review