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      Single cell and tissue-transcriptomic analysis of murine bladders reveals age- and TNFα–dependent but microbiota-independent tertiary lymphoid tissue formation

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          Abstract

          Aging has multifaceted effects on the immune system, but how aging affects tissue-specific immunity is not well-defined. Bladder diseases characterized by chronic inflammation are highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Tissue transcriptomics of unperturbed, young and aged bladders identified a highly altered immune landscape as a fundamental feature of the aging female bladder. Detailed mapping of immune cells using single cell RNA-sequencing revealed novel subsets of macrophages and dendritic cells and unique changes to the immune repertoire in the aged bladder. B and T cells are highly enriched in aged bladders and spontaneously form organized bladder tertiary lymphoid tissues (bTLTs). Naïve, activated, and germinal center B cells and IgA + plasma cells are found within bTLT and associated with increased urinary IgA concentrations. bTLTs form with increasing age and their formation is dependent on TNFα. Microbiota are not required to form bTLT form, as aged germfree mice harbor them. Thus, bTLTs require age-dependent TNFα but are independent of the microbiota. Our results indicate that chronic, age-associated inflammation underlies a fundamental alteration to the bladder and establishes a resource for further investigation of the bladder immune system in homeostasis, aging, and disease.

          One Sentence Summary:

          Mice develop bladder tertiary lymphoid tissue (bTLT) during aging that is dependent on TNFα

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          Most cited references67

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          Proteomics. Tissue-based map of the human proteome.

          Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body. Copyright © 2015, American Association for the Advancement of Science.
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            Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris

            (2018)
            We have created a compendium of single cell transcriptomic data from the model organism Mus musculus comprising more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations, and allow for direct and controlled comparison of gene expression in cell types shared between tissues, such as T-lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3’-end counting, enabled the survey of thousands of cells at relatively low coverage, while the other, FACS-based full length transcript analysis, enabled characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.
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              Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases.

              Human aging is characterized by a chronic, low-grade inflammation, and this phenomenon has been termed as "inflammaging." Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people, as most if not all age-related diseases share an inflammatory pathogenesis. Nevertheless, the precise etiology of inflammaging and its potential causal role in contributing to adverse health outcomes remain largely unknown. The identification of pathways that control age-related inflammation across multiple systems is therefore important in order to understand whether treatments that modulate inflammaging may be beneficial in old people. The session on inflammation of the Advances in Gerosciences meeting held at the National Institutes of Health/National Institute on Aging in Bethesda on October 30 and 31, 2013 was aimed at defining these important unanswered questions about inflammaging. This article reports the main outcomes of this session. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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                Author and article information

                Journal
                101299742
                35518
                Mucosal Immunol
                Mucosal Immunol
                Mucosal immunology
                1933-0219
                1935-3456
                29 April 2020
                04 May 2020
                November 2020
                04 November 2020
                : 13
                : 6
                : 908-918
                Affiliations
                [1 ]Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
                [2 ]McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
                [3 ]Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
                Author notes

                Author contributions

                Conceptualization MML, CW, IUM. Methodology MML, CW, IUM, DMEB. Investigation MML, CW, CS, END. Data analysis MML. Resources IUM, DMEB. Supervision CW, DMEB, IUM. Funding IUM, DMEB. Visualization MML. Writing--original draft MML, IUM. Writing--review & editing MML, CW, DMEB, IUM

                [* ]To whom correspondence should be addressed: Indira U. Mysorekar, Ph.D., Washington University School of Medicine, Depts. of Obstetrics and Gynecology & Pathology and Immunology, 660 S. Euclid Ave., St. Louis, MO 63110, Phone: 314-747-1329, Fax: 314-747-1350, imysorekar@ 123456wustl.edu
                Article
                NIHMS1585777
                10.1038/s41385-020-0290-x
                7572484
                32366865
                e7f6141b-afc4-465a-807c-884ba63e8a68

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Categories
                Article

                Immunology
                single cell rna-sequencing,inflamm-aging,mucosal aging,lower urinary tract symptoms (luts),bladder disease,elderly

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