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      TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice

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          Abstract

          Tumor progression locus 2 (TPL2) (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNA sequencing analysis indicates that protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS (inducible nitric oxide synthase) induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

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          Most cited references69

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          Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

          In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
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            Comprehensive Integration of Single-Cell Data

            Single-cell transcriptomics has transformed our ability to characterize cell states, but deep biological understanding requires more than a taxonomic listing of clusters. As new methods arise to measure distinct cellular modalities, a key analytical challenge is to integrate these datasets to better understand cellular identity and function. Here, we develop a strategy to "anchor" diverse datasets together, enabling us to integrate single-cell measurements not only across scRNA-seq technologies, but also across different modalities. After demonstrating improvement over existing methods for integrating scRNA-seq data, we anchor scRNA-seq experiments with scATAC-seq to explore chromatin differences in closely related interneuron subsets and project protein expression measurements onto a bone marrow atlas to characterize lymphocyte populations. Lastly, we harmonize in situ gene expression and scRNA-seq datasets, allowing transcriptome-wide imputation of spatial gene expression patterns. Our work presents a strategy for the assembly of harmonized references and transfer of information across datasets.
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              Neurotoxic reactive astrocytes are induced by activated microglia

              A reactive astrocyte subtype termed A1 is induced after injury or disease of the central nervous system and subsequently promotes the death of neurons and oligodendrocytes.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                09 August 2023
                2023
                : 12
                : e83451
                Affiliations
                [1 ] Department of Neuroscience, Genentech Inc ( https://ror.org/04gndp242) South San Francisco United States
                [2 ] Department of OMNI Bioinformatics, Genentech Inc ( https://ror.org/04gndp242) South San Francisco United States
                [3 ] Computational Science & Exploratory Analytics, Roche IT, Hoffmann-La Roche Limited Mississauga Canada
                [4 ] Department of Translational Imaging, Genentech Inc ( https://ror.org/04gndp242) South San Francisco United States
                [5 ] Department of Pathology, Genentech Inc ( https://ror.org/04gndp242) South San Francisco United States
                [6 ] Department of Immunology, Genentech Inc ( https://ror.org/04gndp242) South San Francisco United States
                [7 ] Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard ( https://ror.org/042nb2s44) Cambridge United States
                Agency for Science Technology and Research ( https://ror.org/036wvzt09) Singapore
                Yale University ( https://ror.org/03v76x132) United States
                Agency for Science Technology and Research ( https://ror.org/036wvzt09) Singapore
                Agency for Science Technology and Research ( https://ror.org/036wvzt09) Singapore
                University of California, San Diego ( https://ror.org/0168r3w48) United States
                Author information
                https://orcid.org/0000-0002-1180-1554
                https://orcid.org/0000-0002-9273-0574
                https://orcid.org/0000-0003-3059-5132
                Article
                83451
                10.7554/eLife.83451
                10411973
                37555828
                76d527e9-a8b6-4903-bc40-0ac787a6945e
                © 2023, Wang et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 14 September 2022
                : 28 July 2023
                Funding
                No external funding was received for this work.
                Categories
                Research Article
                Immunology and Inflammation
                Neuroscience
                Custom metadata
                Preventing activity of the kinase tumor progression locus 2 modulates microglial activation, reduces T-cell brain infiltration, and is neuroprotective in disease models.

                Life sciences
                tpl2,neurodegeneration,neuroinflammation,microglia,t-cell,single-cell rna sequencing,human,mouse,rat
                Life sciences
                tpl2, neurodegeneration, neuroinflammation, microglia, t-cell, single-cell rna sequencing, human, mouse, rat

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