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

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

doi:10.1038/nn.3531

Cited by 612 publications

(677 citation statements)

References 55 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Yang

Chiu

et al. 2014

The Journal of Immunology

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T cell activation is dependent upon phosphorylation of MAPKs, which play a critical role in the regulation of immune responses. Dual-specificity phosphatase 14 (DUSP14; also known as MKP6) is classified as a MAPK phosphatase. The in vivo functions of DUSP14 remain unclear. Thus, we generated DUSP14-deficient mice and characterized the roles of DUSP14 in T cell activation and immune responses. DUSP14 deficiency in T cells resulted in enhanced T cell proliferation and increased cytokine production upon T cell activation. DUSP14 directly interacted with TGF-β–activated kinase 1 (TAK1)-binding protein 1 (TAB1) and dephosphorylated TAB1 at Ser438, leading to TAB1–TAK1 complex inactivation in T cells. The phosphorylation levels of the TAB1–TAK1 complex and its downstream molecules, including JNK and IκB kinase, were enhanced in DUSP14-deficient T cells upon stimulation. The enhanced JNK and IκB kinase activation in DUSP14-deficient T cells was attenuated by TAB1 short hairpin RNA knockdown. Consistent with that, DUSP14-deficient mice exhibited enhanced immune responses and were more susceptible to experimental autoimmune encephalomyelitis induction. Thus, DUSP14 negatively regulates TCR signaling and immune responses by inhibiting TAB1 activation.

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Section: Discussionmentioning

confidence: 99%

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

Yang

Chiu

et al. 2014

The Journal of Immunology

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“…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].…”

Section: Technical Commentmentioning

confidence: 99%

“…[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.…”

Section: Technical Commentmentioning

confidence: 99%

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

et al. 2016

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“…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.…”

mentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Kannaiyan²,

et al. 2016

Self Cite

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2Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We find that myelin pieces are gradually released from aging myelin sheaths and are subsequently cleared by microglia. Myelin fragmentation increases with age and leads to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial leading to lysosomal storage and contributing to microglia senescence and immune dysfunction in aging.Myelin is formed by oligodendrocytes as a multilamellar structure that encloses segments of axons in the central nervous systems (CNS) of vertebrates 1 . Once myelin is laid down, it is unknown to what extent the sheaths require maintenance and remodeling. Membrane turnover may pose a problem for oligodendrocytes that form up to 80 different myelin sheaths of tightly stacked membrane, but harbour little cytoplasm and few lysosomes, the organelles responsible for membrane degradation. Myelin membrane components are metabolically relatively stable with half-lives on the order of several weeks to months 2,3 . Nevertheless, protein/lipid turnover is, in general, necessary to replace potentially impaired molecules with new functional copies in order to combat functional decline [4][5][6][7] . How do molecules trapped within the numerous layers of tightly compacted membrane enter the degradative system? We tested the hypothesis that myelin degradation occurs in part via shedding of myelin fragments into the extracellular space.We analyzed the white matter of aging mice (up to 24 months) by electron microscopy to search for myelin breakdown products. We detected multilamellar myelin fragments more frequently in the brain of the older mice, of which some were associated with myelin sheaths, while others were in the extracellular space or inside of cells (Supplementary Fig. 1). As fixation artefacts frequently affect the appearance of myelin in chemically fixed tissue, we used high-pressure freezing to fix tissue and confirmed the progressive accumulation of multilamellar myelin fragments with age ( Fig. 1a,b).Since some of these myelin fragments were found inside cells, we performed immunhistochemistry to determine whether microglia, the brain phagocytes [8][9][10] , were responsible for the uptake of myelin fragments. An increasing number of myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactive puncta co-localized with Iba1-positive microglia with age ( Fig. 1c, Supplementary Fig. 1).Three-dimensional reconstructions demonstrated that immunoreactive puncta were present inside of microglia (Fig. 1c). Since our results suggested that microglia clear away the myelin fragments that accumulate in the 3 aging brain, we compared microglia number and appearance in young and old animals. Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2). Next, the morphology of lysosomes was evalua...

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

Cited by 612 publications

References 55 publications

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

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

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

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

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