GABA signaling enforces intestinal germinal center B cell differentiation
Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA⁺ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC)...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2022-11, Vol.119 (44), p.1-11 |
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| creator | Liao, Yuexia Fan, Lijuan Bin, Peng Zhu, Congrui Chen, Qingyi Cai, Yepeng Duan, Jielin Cai, Qian Han, Wei Ding, Shizhen Hu, Xiangyu Zhang, Yiran Yin, Yulong Ren, Wenkai |
| description | Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA⁺ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA–mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling–mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN. |
| doi_str_mv | 10.1073/pnas.2215921119 |
| format | Article |
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Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA–mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling–mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2215921119</identifier><identifier>PMID: 36279432</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Biological Sciences ; Butyric acid ; Cell activation ; Cell Differentiation ; Differentiation (biology) ; gamma-Aminobutyric Acid - metabolism ; Germinal Center - metabolism ; Germinal centers ; Glomerulonephritis, IGA ; Immunoglobulin A ; Immunoglobulin A - metabolism ; Intestine ; Lymphocytes B ; Mammals ; Mechanistic Target of Rapamycin Complex 1 - metabolism ; Mice ; Mucosal immunity ; Nephropathy ; Neurotransmitters ; Pathogenesis ; Rapamycin ; Signaling ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; γ-Aminobutyric acid</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2022-11, Vol.119 (44), p.1-11</ispartof><rights>Copyright © 2022 the Author(s)</rights><rights>Copyright National Academy of Sciences Nov 1, 2022</rights><rights>Copyright © 2022 the Author(s). Published by PNAS. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-8ee990e9ee00e4ba56329438d932146aaf6891c7de1d58a89392d4471cfe736a3</citedby><cites>FETCH-LOGICAL-c443t-8ee990e9ee00e4ba56329438d932146aaf6891c7de1d58a89392d4471cfe736a3</cites><orcidid>0000-0001-8446-5400</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636909/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9636909/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36279432$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liao, Yuexia</creatorcontrib><creatorcontrib>Fan, Lijuan</creatorcontrib><creatorcontrib>Bin, Peng</creatorcontrib><creatorcontrib>Zhu, Congrui</creatorcontrib><creatorcontrib>Chen, Qingyi</creatorcontrib><creatorcontrib>Cai, Yepeng</creatorcontrib><creatorcontrib>Duan, Jielin</creatorcontrib><creatorcontrib>Cai, Qian</creatorcontrib><creatorcontrib>Han, Wei</creatorcontrib><creatorcontrib>Ding, Shizhen</creatorcontrib><creatorcontrib>Hu, Xiangyu</creatorcontrib><creatorcontrib>Zhang, Yiran</creatorcontrib><creatorcontrib>Yin, Yulong</creatorcontrib><creatorcontrib>Ren, Wenkai</creatorcontrib><title>GABA signaling enforces intestinal germinal center B cell differentiation</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA⁺ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA–mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling–mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN.</description><subject>Animals</subject><subject>Biological Sciences</subject><subject>Butyric acid</subject><subject>Cell activation</subject><subject>Cell Differentiation</subject><subject>Differentiation (biology)</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Germinal Center - metabolism</subject><subject>Germinal centers</subject><subject>Glomerulonephritis, IGA</subject><subject>Immunoglobulin A</subject><subject>Immunoglobulin A - metabolism</subject><subject>Intestine</subject><subject>Lymphocytes B</subject><subject>Mammals</subject><subject>Mechanistic Target of Rapamycin Complex 1 - metabolism</subject><subject>Mice</subject><subject>Mucosal immunity</subject><subject>Nephropathy</subject><subject>Neurotransmitters</subject><subject>Pathogenesis</subject><subject>Rapamycin</subject><subject>Signaling</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>γ-Aminobutyric acid</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1P3DAQxS3UChbaMyeqSFy4BMYfcTyXSgsCioTEhZ4tk0wWr7Lx1s4i8d_jdOmW9uTRzM_j9_wYO-ZwzqGWF-vBpXMheIWCc457bMYBeakVwic2AxB1aZRQB-wwpSUAYGVgnx1ILWpUUszY3e38cl4kvxhc74dFQUMXYkOp8MNIafS5XSworn4XDeVmLC5z0fdF67uOYm55N_owfGGfO9cn-vp-HrGfN9ePVz_K-4fbu6v5fdkoJcfSECECIREAqSdXaSmyFNOiFFxp5zptkDd1S7ytjDMoUbRK1bzpqJbaySP2fbt3vXlaUTtpiq636-hXLr7a4Lz9dzL4Z7sILxa11AiYF5y9L4jh1yabtCufJkduoLBJVtTCKK1lXWX09D90GTYxf8VESW64lFJl6mJLNTGkFKnbieFgp5jsFJP9G1O-8e2jhx3_J5cMnGyBZRpD3M2zNEDIT74BtA-X9g</recordid><startdate>20221101</startdate><enddate>20221101</enddate><creator>Liao, Yuexia</creator><creator>Fan, Lijuan</creator><creator>Bin, Peng</creator><creator>Zhu, Congrui</creator><creator>Chen, Qingyi</creator><creator>Cai, Yepeng</creator><creator>Duan, Jielin</creator><creator>Cai, Qian</creator><creator>Han, Wei</creator><creator>Ding, Shizhen</creator><creator>Hu, Xiangyu</creator><creator>Zhang, Yiran</creator><creator>Yin, Yulong</creator><creator>Ren, Wenkai</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-8446-5400</orcidid></search><sort><creationdate>20221101</creationdate><title>GABA signaling enforces intestinal germinal center B cell differentiation</title><author>Liao, Yuexia ; 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Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA–mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling–mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>36279432</pmid><doi>10.1073/pnas.2215921119</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-8446-5400</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biological Sciences Butyric acid Cell activation Cell Differentiation Differentiation (biology) gamma-Aminobutyric Acid - metabolism Germinal Center - metabolism Germinal centers Glomerulonephritis, IGA Immunoglobulin A Immunoglobulin A - metabolism Intestine Lymphocytes B Mammals Mechanistic Target of Rapamycin Complex 1 - metabolism Mice Mucosal immunity Nephropathy Neurotransmitters Pathogenesis Rapamycin Signaling TOR protein TOR Serine-Threonine Kinases - metabolism γ-Aminobutyric acid |
| title | GABA signaling enforces intestinal germinal center B cell differentiation |
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