GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans
GABAergic neurotransmission constitutes a major inhibitory signaling mechanism that plays crucial roles in central nervous system physiology and immune cell immunomodulation. However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junction...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2021-05, Vol.118 (20), p.1-10 |
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| creator | Zheng, Zhongfan Zhang, Xiumei Liu, Junqiang He, Ping Zhang, Shan Zhang, Yongning Gao, Jie Yang, Shengmei Kang, Na Afridi, Muhammad Irfan Gao, Shangbang Chen, Chunhong Tu, Haijun |
| description | GABAergic neurotransmission constitutes a major inhibitory signaling mechanism that plays crucial roles in central nervous system physiology and immune cell immunomodulation. However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junctions (NMJs) of Caenorhabditis elegans results in enhanced resistance to pathogens, whereas pathogen infection enhances the strength of GABAergic transmission. GABAergic synapses control innate immunity in a manner dependent on the FOXO/DAF-16 but not the p38/PMK-1 pathway. Our data reveal that the insulin-like peptide INS-31 level was dramatically decreased in the GABAergic NMJ GABAₐR-deficient unc-49 mutant compared with wild-type animals. C. elegans with ins-31 knockdown or loss of function exhibited enhanced resistance to Pseudomonas aeruginosa PA14 exposure. INS-31 may act downstream of GABAergic NMJs and in body wall muscle to control intestinal innate immunity in a cell-nonautonomous manner. Our results reveal a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo. |
| doi_str_mv | 10.1073/pnas.2021063118 |
| format | Article |
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However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junctions (NMJs) of Caenorhabditis elegans results in enhanced resistance to pathogens, whereas pathogen infection enhances the strength of GABAergic transmission. GABAergic synapses control innate immunity in a manner dependent on the FOXO/DAF-16 but not the p38/PMK-1 pathway. Our data reveal that the insulin-like peptide INS-31 level was dramatically decreased in the GABAergic NMJ GABAₐR-deficient unc-49 mutant compared with wild-type animals. C. elegans with ins-31 knockdown or loss of function exhibited enhanced resistance to Pseudomonas aeruginosa PA14 exposure. INS-31 may act downstream of GABAergic NMJs and in body wall muscle to control intestinal innate immunity in a cell-nonautonomous manner. Our results reveal a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2021063118</identifier><identifier>PMID: 33972423</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Biological Sciences ; Body wall ; Caenorhabditis elegans ; Central nervous system ; Forkhead protein ; Immune system ; Immunity ; Immunomodulation ; Innate immunity ; Insulin ; Intestine ; Muscles ; Nematodes ; Neuromuscular junctions ; Neurotransmission ; Pathogens ; Pseudomonas aeruginosa ; Signaling ; Synapses ; Synaptic strength ; Worms ; γ-Aminobutyric acid ; γ-Aminobutyric acid A receptors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2021-05, Vol.118 (20), p.1-10</ispartof><rights>Copyright National Academy of Sciences May 18, 2021</rights><rights>2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-4390604abf808365cc000f98719c179c23aa1ccf0bd063222e7ac2e1f900d69f3</citedby><cites>FETCH-LOGICAL-c443t-4390604abf808365cc000f98719c179c23aa1ccf0bd063222e7ac2e1f900d69f3</cites><orcidid>0000-0003-1365-4620 ; 0000-0002-6575-7747 ; 0000-0002-2953-487X ; 0000-0001-6652-3056 ; 0000-0002-5975-7855 ; 0000-0001-5431-4628 ; 0000-0002-8960-856X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27040428$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27040428$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,725,778,782,801,883,27907,27908,53774,53776,58000,58233</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33972423$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zheng, Zhongfan</creatorcontrib><creatorcontrib>Zhang, Xiumei</creatorcontrib><creatorcontrib>Liu, Junqiang</creatorcontrib><creatorcontrib>He, Ping</creatorcontrib><creatorcontrib>Zhang, Shan</creatorcontrib><creatorcontrib>Zhang, Yongning</creatorcontrib><creatorcontrib>Gao, Jie</creatorcontrib><creatorcontrib>Yang, Shengmei</creatorcontrib><creatorcontrib>Kang, Na</creatorcontrib><creatorcontrib>Afridi, Muhammad Irfan</creatorcontrib><creatorcontrib>Gao, Shangbang</creatorcontrib><creatorcontrib>Chen, Chunhong</creatorcontrib><creatorcontrib>Tu, Haijun</creatorcontrib><title>GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>GABAergic neurotransmission constitutes a major inhibitory signaling mechanism that plays crucial roles in central nervous system physiology and immune cell immunomodulation. However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junctions (NMJs) of Caenorhabditis elegans results in enhanced resistance to pathogens, whereas pathogen infection enhances the strength of GABAergic transmission. GABAergic synapses control innate immunity in a manner dependent on the FOXO/DAF-16 but not the p38/PMK-1 pathway. Our data reveal that the insulin-like peptide INS-31 level was dramatically decreased in the GABAergic NMJ GABAₐR-deficient unc-49 mutant compared with wild-type animals. C. elegans with ins-31 knockdown or loss of function exhibited enhanced resistance to Pseudomonas aeruginosa PA14 exposure. INS-31 may act downstream of GABAergic NMJs and in body wall muscle to control intestinal innate immunity in a cell-nonautonomous manner. Our results reveal a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.</description><subject>Biological Sciences</subject><subject>Body wall</subject><subject>Caenorhabditis elegans</subject><subject>Central nervous system</subject><subject>Forkhead protein</subject><subject>Immune system</subject><subject>Immunity</subject><subject>Immunomodulation</subject><subject>Innate immunity</subject><subject>Insulin</subject><subject>Intestine</subject><subject>Muscles</subject><subject>Nematodes</subject><subject>Neuromuscular junctions</subject><subject>Neurotransmission</subject><subject>Pathogens</subject><subject>Pseudomonas aeruginosa</subject><subject>Signaling</subject><subject>Synapses</subject><subject>Synaptic strength</subject><subject>Worms</subject><subject>γ-Aminobutyric acid</subject><subject>γ-Aminobutyric acid A receptors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNpdkc1v1DAQxS0EotvCmRMoEhcuaccfSewL0rKiBakSFzhbs14n9SpxgieptP89Xm1ZPk5jzfzmaZ4fY284XHNo5M0Uka4FCA615Fw_YysOhpe1MvCcrQBEU2ol1AW7JNoDgKk0vGQXUppGKCFXrL1bf1r71AVX0CHiRJ4KWqYpeaIixNnTHCL2-Rlx9kUYhiWG-VA8Bsw9WvoQCwpdRkLscqfYoI9jesDtLsyBCt_7DiO9Yi9a7Mm_fqpX7Mft5--bL-X9t7uvm_V96ZSSc6mkgRoUblsNWtaVc_nm1uiGG8cb44RE5M61sN1lw0II36ATnrcGYFebVl6xjyfdadkOfud8nBP2dkphwHSwIwb77ySGB9uNj1bzqjFcZ4EPTwJp_Llk93YI5HzfY_TjQlZUoqorXuk6o-__Q_fjkvJPHCkJFZdGq0zdnCiXRqLk2_MxHOwxQ3vM0P7JMG-8-9vDmf8dWgbenoA9zWM6z0UDCpTQ8heyy6N4</recordid><startdate>20210518</startdate><enddate>20210518</enddate><creator>Zheng, Zhongfan</creator><creator>Zhang, Xiumei</creator><creator>Liu, Junqiang</creator><creator>He, Ping</creator><creator>Zhang, Shan</creator><creator>Zhang, Yongning</creator><creator>Gao, Jie</creator><creator>Yang, Shengmei</creator><creator>Kang, Na</creator><creator>Afridi, Muhammad Irfan</creator><creator>Gao, Shangbang</creator><creator>Chen, Chunhong</creator><creator>Tu, Haijun</creator><general>National Academy of Sciences</general><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/0000-0003-1365-4620</orcidid><orcidid>https://orcid.org/0000-0002-6575-7747</orcidid><orcidid>https://orcid.org/0000-0002-2953-487X</orcidid><orcidid>https://orcid.org/0000-0001-6652-3056</orcidid><orcidid>https://orcid.org/0000-0002-5975-7855</orcidid><orcidid>https://orcid.org/0000-0001-5431-4628</orcidid><orcidid>https://orcid.org/0000-0002-8960-856X</orcidid></search><sort><creationdate>20210518</creationdate><title>GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans</title><author>Zheng, Zhongfan ; 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However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junctions (NMJs) of Caenorhabditis elegans results in enhanced resistance to pathogens, whereas pathogen infection enhances the strength of GABAergic transmission. GABAergic synapses control innate immunity in a manner dependent on the FOXO/DAF-16 but not the p38/PMK-1 pathway. Our data reveal that the insulin-like peptide INS-31 level was dramatically decreased in the GABAergic NMJ GABAₐR-deficient unc-49 mutant compared with wild-type animals. C. elegans with ins-31 knockdown or loss of function exhibited enhanced resistance to Pseudomonas aeruginosa PA14 exposure. INS-31 may act downstream of GABAergic NMJs and in body wall muscle to control intestinal innate immunity in a cell-nonautonomous manner. Our results reveal a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>33972423</pmid><doi>10.1073/pnas.2021063118</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-1365-4620</orcidid><orcidid>https://orcid.org/0000-0002-6575-7747</orcidid><orcidid>https://orcid.org/0000-0002-2953-487X</orcidid><orcidid>https://orcid.org/0000-0001-6652-3056</orcidid><orcidid>https://orcid.org/0000-0002-5975-7855</orcidid><orcidid>https://orcid.org/0000-0001-5431-4628</orcidid><orcidid>https://orcid.org/0000-0002-8960-856X</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Biological Sciences Body wall Caenorhabditis elegans Central nervous system Forkhead protein Immune system Immunity Immunomodulation Innate immunity Insulin Intestine Muscles Nematodes Neuromuscular junctions Neurotransmission Pathogens Pseudomonas aeruginosa Signaling Synapses Synaptic strength Worms γ-Aminobutyric acid γ-Aminobutyric acid A receptors |
| title | GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans |
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