{
    "abstract": "Ectopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms underlying TLT expansion and their effect on renal regeneration remain unclear. The authors report that single-nucleus RNA sequencing and validation experiments demonstrate that TLTs potentially amplify inflammation in aged injured kidneys. Lymphocytes within TLTs promote proinflammatory phenotypes of the surrounding proximal tubules and fibroblasts within the TLTs via proinflammatory cytokine production. These proinflammatory parenchymal cells then interact with immune cells by chemokine or cytokine production. Such cell-cell interactions potentially increase inflammation, expand TLTs, and exacerbate kidney injury. These findings help illuminate renal TLT pathology and suggest potential therapeutic targets.\nEctopic lymphoid structures called tertiary lymphoid tissues (TLTs) develop in several kidney diseases and are associated with poor renal prognosis. However, the mechanisms that expand TLTs and underlie exacerbation of kidney injury remain unclear.\nWe performed single-nucleus RNA sequencing (snRNA-seq) on aged mouse kidneys with TLTs after ischemia-reperfusion injury. The results were validated using immunostaining, in situ hybridization of murine and human kidneys, and in vitro experiments.\nUsing snRNA-seq, we identified proinflammatory and profibrotic Vcam1+ injured proximal tubules (PTs) with NF \u03ba B and IFN-inducible transcription factor activation. VCAM1 + PTs were preferentially localized around TLTs and drove inflammation and fibrosis via the production of multiple chemokines or cytokines. Lymphocytes within TLTs expressed Tnf and Ifng at high levels, which synergistically upregulated VCAM1 and chemokine expression in cultured PT cells. In addition, snRNA-seq also identified proinflammatory and profibrotic fibroblasts, which resided within and outside TLTs, respectively. Proinflammatory fibroblasts exhibited STAT1 activation and various chemokine or cytokine production, including CXCL9/CXCL10 and B cell-activating factor, contributing to lymphocyte recruitment and survival. IFN \u03b3 upregulated the expression of these molecules in cultured fibroblasts in a STAT1-dependent manner, indicating potential bidirectional interactions between IFN \u03b3 -producing CXCR3 + T cells and proinflammatory fibroblasts within TLTs. The cellular and molecular components described in this study were confirmed in human kidneys with TLTs.\nThese findings suggest that TLTs potentially amplify inflammation by providing a microenvironment that allows intense interactions between renal parenchymal and immune cells. These interactions may serve as novel therapeutic targets in kidney diseases involving TLT formation.",
    "authors": [
        {
            "affiliation": "Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.",
            "firstname": "Takahisa",
            "initials": "T",
            "lastname": "Yoshikawa"
        },
        {
            "affiliation": "Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.\nRIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.\nInstitute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.",
            "firstname": "Akiko",
            "initials": "A",
            "lastname": "Oguchi"
        },
        {
            "affiliation": "Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.\nInstitute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.",
            "firstname": "Naoya",
            "initials": "N",
            "lastname": "Toriu"
        },
        {
            "affiliation": "Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.",
            "firstname": "Yuki",
            "initials": "Y",
            "lastname": "Sato"
        },
        {
            "affiliation": "Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.",
            "firstname": "Takashi",
            "initials": "T",
            "lastname": "Kobayashi"
        },
        {
            "affiliation": "Department of Urology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.",
            "firstname": "Osamu",
            "initials": "O",
            "lastname": "Ogawa"
        },
        {
            "affiliation": "Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.",
            "firstname": "Hironori",
            "initials": "H",
            "lastname": "Haga"
        },
        {
            "affiliation": "Department of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.",
            "firstname": "Satoko",
            "initials": "S",
            "lastname": "Sakurai"
        },
        {
            "affiliation": "Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.\nDepartment of Life Science Frontiers, Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan.\nMedical-risk Avoidance based on iPS Cells Team, RIKEN Center for Advanced Intelligence Project (AIP), Kyoto, Japan.",
            "firstname": "Takuya",
            "initials": "T",
            "lastname": "Yamamoto"
        },
        {
            "affiliation": "RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.\nInstitute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.\nIFOM-ETS, Milan, Italy.",
            "firstname": "Yasuhiro",
            "initials": "Y",
            "lastname": "Murakawa"
        },
        {
            "affiliation": "Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.\nInstitute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.",
            "firstname": "Motoko",
            "initials": "M",
            "lastname": "Yanagita"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2023 The Author. Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.",
    "doi": "10.1681/ASN.0000000000000202\n10.3389/fimmu.2019.02938\n10.1038/nrrheum.2016.217\n10.1038/s41568-019-0144-6\n10.1093/ndt/gfab212\n10.1056/NEJMoa035588\n10.1681/ASN.2021050715\n10.2215/CJN.01150113\n10.1155/2012/967584\n10.1172/jci.insight.87680\n10.1172/JCI146071\n10.1126/science.aar2131\n10.1038/s41586-020-2941-1\n10.1681/ASN.2019080832\n10.1073/pnas.2005477117\n10.1073/pnas.2026684118\n10.1016/j.kint.2020.02.023\n10.1016/j.cell.2019.05.031\n10.1016/j.cels.2019.03.003\n10.1093/gigascience/giaa151\n10.1681/ASN.2019040415\n10.1038/nrneph.2014.170\n10.1681/ASN.2018090931\n10.1126/sciadv.aaw8330\n10.1016/j.coi.2017.03.006\n10.1016/j.devcel.2019.10.005\n10.1681/ASN.2018090912\n10.1038/ncomms8866\n10.1038/s41596-020-0292-x\n10.1038/nmeth.4463\n10.1038/nmeth.4150\n10.1186/1471-2105-14-128\n10.1093/nar/gkw377\n10.1002/cpz1.90\n10.1093/nar/28.1.27\n10.1093/nar/gkaa970\n10.1038/75556\n10.1093/nar/gkaa1113\n10.1093/bioinformatics/bts635\n10.1186/1471-2105-12-323\n10.1186/s13059-014-0550-8\n10.1038/srep03355\n10.1093/nar/gky354\n10.1126/scitranslmed.abe0407\n10.1016/j.kint.2015.12.037\n10.1681/ASN.2019010068\n10.1038/79738\n10.1681/ASN.2019020112\n10.1681/ASN.2005040364\n10.3389/fimmu.2020.00976\n10.4049/jimmunol.169.5.2685\n10.4049/jimmunol.168.7.3195\n10.1186/1756-0500-7-345\n10.1159/000188943\n10.1371/journal.pone.0079839\n10.1002/sctm.20-0392\n10.1038/s41467-019-09728-3\n10.1038/s41467-021-26530-2\n10.1038/s41598-017-08703-6\n10.1084/jem.187.4.655\n10.1126/science.1061965\n10.1084/jem.189.11.1747\n10.1038/s41467-021-22368-w\n10.1681/ASN.2016050508\n10.1172/jci.insight.121886\n10.1016/j.cell.2020.11.025\n10.1038/s41586-021-04221-8\n10.1038/s41598-020-73147-4\n10.1038/nrrheum.2013.4\n10.1038/nrrheum.2017.51\n10.3389/fimmu.2021.790125\n10.1073/pnas.1905301116\n10.1038/s41467-022-29701-x\n10.1111/ajt.16880\n10.1038/s41581-023-00706-z",
    "journal": "Journal of the American Society of Nephrology : JASN",
    "keywords": [],
    "methods": null,
    "publication_date": "2023-08-07",
    "pubmed_id": "37548710\n31921189\n28202919\n31092904\n34245300\n12853585\n34725107\n24262509\n22792121\n27699223\n34813503\n29622724\n33176333\n31818909\n32571916\n34183416\n32473779\n31178118\n30954475\n33367645\n31253652\n25266210\n30948627\n31457092\n28319733\n31689386\n30510133\n26198319\n32103204\n28991892\n28114287\n23586463\n27141961\n33780170\n10592173\n33125081\n10802651\n33290552\n23104886\n21816040\n25516281\n24284873\n29762716\n34349032\n8644858\n26924050\n31315923\n11017100\n30867246\n16382019\n32547545\n12193742\n11907072\n24906443\n8730425\n24244568\n33951342\n30988302\n34737275\n28801610\n9463416\n11509692\n10359578\n33850129\n28739648\n30232288\n33278357\n34912121\n33004899\n23399692\n28360424\n34868078\n31213547\n35440634\n34726836\n37046081",
    "results": "Using snRNA-seq, we identified proinflammatory and profibrotic Vcam1+ injured proximal tubules (PTs) with NF \u03ba B and IFN-inducible transcription factor activation. VCAM1 + PTs were preferentially localized around TLTs and drove inflammation and fibrosis via the production of multiple chemokines or cytokines. Lymphocytes within TLTs expressed Tnf and Ifng at high levels, which synergistically upregulated VCAM1 and chemokine expression in cultured PT cells. In addition, snRNA-seq also identified proinflammatory and profibrotic fibroblasts, which resided within and outside TLTs, respectively. Proinflammatory fibroblasts exhibited STAT1 activation and various chemokine or cytokine production, including CXCL9/CXCL10 and B cell-activating factor, contributing to lymphocyte recruitment and survival. IFN \u03b3 upregulated the expression of these molecules in cultured fibroblasts in a STAT1-dependent manner, indicating potential bidirectional interactions between IFN \u03b3 -producing CXCR3 + T cells and proinflammatory fibroblasts within TLTs. The cellular and molecular components described in this study were confirmed in human kidneys with TLTs.",
    "title": "Tertiary Lymphoid Tissues Are Microenvironments with Intensive Interactions between Immune Cells and Proinflammatory Parenchymal Cells in Aged Kidneys.",
    "xml": "<Element 'PubmedArticle' at 0x7885021560c0>"
}