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

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.

Dual-Specificity Phosphatase 14 (DUSP14/MKP6) Negatively Regulates TCR Signaling by Inhibiting TAB1 Activation

“…Thus, the enhanced Th1 differentiation in vitro in DUSP14-deficient T cells may be due to the effect of ERK2 hyperactivation. The results from TAK1-small interfering RNA knockdown in myeloid cells and TAK1-conditional KO in glia cells suggest that TAK1 is required for Th1 and Th17 differentiation and in vivo induction of autoimmunity (29,30). ERK1-deficient mice in the 129 Sv, but not the C57BL/6, genetic background are more susceptible to EAE induction (31).…”

Neurons exhibit Lyz2 promoter activity in vivo: Implications for using LysM‐Cre mice in myeloid cell research

“…Furthermore, LysM-Cre mice have been used to genetically target myeloid cells or microglia (Supporting Information refs. [6][7][8][9][10]). However, recently LysM-Cre mice have been controversially discussed to target microglia [7,8].…”

“…[6][7][8][9][10]). However, recently LysM-Cre mice have been controversially discussed to target microglia [7,8]. Therefore, we aimed at characterizing LysM-Cre positive cells by breeding LysM-Cre mice to tdTomato reporter mice [9] resulting in bright tdTomato expression in cells that either currently express Cre, driven by the endogenous LysM promoter, or have arisen from LysM-expressing cells.…”

Age-related myelin degradation burdens the clearance function of microglia during aging

“…5). These results not only show that microglia actively clear away myelin, but also indicate that this process is associated with the accumulation of undegradable lysosomal aggregates in microglia of the aging brain.Given that microglia appear to be involved in myelin clearance, we reasoned that blocking lysosomal degradation should lead to the accumulation of myelin fragments in younger mice.Thus, we generated conditional Rab7 KO mice using CX 3 CR1 CreER animals to specifically interfere with lysosomal function in microglia/macrophage 16,17 . Cell-specific recombination was confirmed by crossing mice with TdTomato reporter line, which showed TdTomato expression in more than 90% of the microglia (Supplementary Fig.…”

“…Thus, we generated conditional Rab7 KO mice using CX 3 CR1 CreER animals to specifically interfere with lysosomal function in microglia/macrophage 16,17 . Cell-specific recombination was confirmed by crossing mice with TdTomato reporter line, which showed TdTomato expression in more than 90% of the microglia (Supplementary Fig.…”