Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit
Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2022-05, Vol.119 (22), p.1-11 |
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| creator | Caravaca, April S. Gallina, Alessandro L. Tarnawski, Laura Shavva, Vladimir S. Colas, Romain A. Dalli, Jesmond Malin, Stephen G. Hult, Henrik Arnardottir, Hildur Olofsson, Peder S. |
| description | Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR. |
| doi_str_mv | 10.1073/pnas.2023285119 |
| format | Article |
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Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR.</description><identifier>ISSN: 0027-8424</identifier><identifier>ISSN: 1091-6490</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.2023285119</identifier><identifier>PMID: 35622894</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>a7nAChR gene ; Alox15 gene ; Alox15 protein ; alpha7 Nicotinic Acetylcholine Receptor ; alpha7 Nicotinic Acetylcholine Receptor - genetics ; animal ; animal cell ; animal experiment ; animal model ; animal tissue ; Animals ; Arachidonate 12-Lipoxygenase ; Arachidonate 12-Lipoxygenase - genetics ; Arachidonate 12-Lipoxygenase - metabolism ; Arachidonate 15-Lipoxygenase ; Arachidonate 15-Lipoxygenase - genetics ; Arachidonate 15-Lipoxygenase - metabolism ; autacoid ; autonomic reflex ; Biological Sciences ; Biosynthesis ; bungarotoxin receptor ; cervonic acid ; Cholinergics ; controlled study ; disease duration ; Disease Models, Animal ; docosapentaenoic acid ; efferocytosis ; ex vivo study ; Exudates ; Exudation ; gene ; genetics ; In vivo methods and tests ; in vivo study ; Inflammation ; Inflammation - therapy ; Inflammation Mediators ; Inflammation Mediators - metabolism ; Inflammatory diseases ; Leukocytes (neutrophilic) ; lipid mediators ; lipidomics ; Lipids ; male ; Mice ; Mice, Mutant Strains ; mouse ; Nerves ; nervous system inflammation ; neuroinflammation ; nonhuman ; Peritoneum ; peritoneum exudate ; Peritonitis ; physiology ; Reflexes ; Stimulation ; surgical technique ; Vagus Nerve ; Vagus Nerve - physiology ; Vagus Nerve Stimulation ; zymosan</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2022-05, Vol.119 (22), p.1-11</ispartof><rights>Copyright © 2022 the Author(s)</rights><rights>Copyright National Academy of Sciences May 31, 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-c519t-76e59fb1d0e5de3f05a8c268f2c917dfdd1b41cab50673f0a0302a463b77d2843</citedby><cites>FETCH-LOGICAL-c519t-76e59fb1d0e5de3f05a8c268f2c917dfdd1b41cab50673f0a0302a463b77d2843</cites><orcidid>0000-0001-6328-3640 ; 0000-0001-7723-9579 ; 0000-0002-5163-3946 ; 0000-0002-0127-8309 ; 0000-0001-9210-121X ; 0000-0003-3473-5948</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/PMC9295760/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9295760/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35622894$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-324380$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:153479786$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Caravaca, April S.</creatorcontrib><creatorcontrib>Gallina, Alessandro L.</creatorcontrib><creatorcontrib>Tarnawski, Laura</creatorcontrib><creatorcontrib>Shavva, Vladimir S.</creatorcontrib><creatorcontrib>Colas, Romain A.</creatorcontrib><creatorcontrib>Dalli, Jesmond</creatorcontrib><creatorcontrib>Malin, Stephen G.</creatorcontrib><creatorcontrib>Hult, Henrik</creatorcontrib><creatorcontrib>Arnardottir, Hildur</creatorcontrib><creatorcontrib>Olofsson, Peder S.</creatorcontrib><title>Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR.</description><subject>a7nAChR gene</subject><subject>Alox15 gene</subject><subject>Alox15 protein</subject><subject>alpha7 Nicotinic Acetylcholine Receptor</subject><subject>alpha7 Nicotinic Acetylcholine Receptor - genetics</subject><subject>animal</subject><subject>animal cell</subject><subject>animal experiment</subject><subject>animal model</subject><subject>animal tissue</subject><subject>Animals</subject><subject>Arachidonate 12-Lipoxygenase</subject><subject>Arachidonate 12-Lipoxygenase - genetics</subject><subject>Arachidonate 12-Lipoxygenase - metabolism</subject><subject>Arachidonate 15-Lipoxygenase</subject><subject>Arachidonate 15-Lipoxygenase - genetics</subject><subject>Arachidonate 15-Lipoxygenase - metabolism</subject><subject>autacoid</subject><subject>autonomic reflex</subject><subject>Biological Sciences</subject><subject>Biosynthesis</subject><subject>bungarotoxin receptor</subject><subject>cervonic acid</subject><subject>Cholinergics</subject><subject>controlled study</subject><subject>disease duration</subject><subject>Disease Models, Animal</subject><subject>docosapentaenoic acid</subject><subject>efferocytosis</subject><subject>ex vivo study</subject><subject>Exudates</subject><subject>Exudation</subject><subject>gene</subject><subject>genetics</subject><subject>In vivo methods and tests</subject><subject>in vivo study</subject><subject>Inflammation</subject><subject>Inflammation - therapy</subject><subject>Inflammation Mediators</subject><subject>Inflammation Mediators - metabolism</subject><subject>Inflammatory diseases</subject><subject>Leukocytes (neutrophilic)</subject><subject>lipid mediators</subject><subject>lipidomics</subject><subject>Lipids</subject><subject>male</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>mouse</subject><subject>Nerves</subject><subject>nervous system inflammation</subject><subject>neuroinflammation</subject><subject>nonhuman</subject><subject>Peritoneum</subject><subject>peritoneum exudate</subject><subject>Peritonitis</subject><subject>physiology</subject><subject>Reflexes</subject><subject>Stimulation</subject><subject>surgical technique</subject><subject>Vagus Nerve</subject><subject>Vagus Nerve - physiology</subject><subject>Vagus Nerve Stimulation</subject><subject>zymosan</subject><issn>0027-8424</issn><issn>1091-6490</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNp9kstu1DAYhSMEokNhzQpkqRs2aX13vEEaDVepEhKCbi0ncWY8Teyp7Qx0ySPxIjwTDhkGyoKFZes_3zmyrVMUTxE8R1CQi53T8RxDTHDFEJL3igWCEpWcSni_WECIRVlRTE-KRzFuIYSSVfBhcUIYx7iSdFF8u9LrMQJnwt6AmOww9jpZ78Au-MEnE0Ew0ffjr5nvgHVdr4dhZupboMFgmo12Ng4gbXTKwN73--xb9v4rYkC7NkfcjDbnZMKAH9-FW642H0Ec69HZ9Lh40Ok-mieH_bT4_Ob1p9W78vLD2_er5WXZMCRTKbhhsqtRCw1rDekg01WDedXhRiLRdm2LaooaXTPIRZY1JBBrykktRIsrSk6Lcs6NX8xurNUu2EGHW-W1VYfRdT4ZRRlBef2Pf2WvlsqHtbpOG0UwJRXM_MuZz_Bg2sa4FHR_x3ZXcXaj1n6vJJZM8CngxSEg-JvRxKQGGxvT99oZP0aFuUCYM86rjJ79g279GFz-vokiHEtKp8CLmWqCjzGY7ngZBNVUHzXVR_2pT3Y8__sNR_53XzLwbAa2Mflw1LFADEMkyE8FCs72</recordid><startdate>20220531</startdate><enddate>20220531</enddate><creator>Caravaca, April S.</creator><creator>Gallina, Alessandro L.</creator><creator>Tarnawski, Laura</creator><creator>Shavva, Vladimir S.</creator><creator>Colas, Romain A.</creator><creator>Dalli, Jesmond</creator><creator>Malin, Stephen G.</creator><creator>Hult, Henrik</creator><creator>Arnardottir, Hildur</creator><creator>Olofsson, Peder S.</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><scope>ADTPV</scope><scope>AFDQA</scope><scope>AOWAS</scope><scope>D8T</scope><scope>D8V</scope><scope>ZZAVC</scope><orcidid>https://orcid.org/0000-0001-6328-3640</orcidid><orcidid>https://orcid.org/0000-0001-7723-9579</orcidid><orcidid>https://orcid.org/0000-0002-5163-3946</orcidid><orcidid>https://orcid.org/0000-0002-0127-8309</orcidid><orcidid>https://orcid.org/0000-0001-9210-121X</orcidid><orcidid>https://orcid.org/0000-0003-3473-5948</orcidid></search><sort><creationdate>20220531</creationdate><title>Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit</title><author>Caravaca, April S. ; Gallina, Alessandro L. ; Tarnawski, Laura ; Shavva, Vladimir S. ; Colas, Romain A. ; Dalli, Jesmond ; Malin, Stephen G. ; Hult, Henrik ; Arnardottir, Hildur ; Olofsson, Peder S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c519t-76e59fb1d0e5de3f05a8c268f2c917dfdd1b41cab50673f0a0302a463b77d2843</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>a7nAChR gene</topic><topic>Alox15 gene</topic><topic>Alox15 protein</topic><topic>alpha7 Nicotinic Acetylcholine Receptor</topic><topic>alpha7 Nicotinic Acetylcholine Receptor - 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PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2022-05-31</date><risdate>2022</risdate><volume>119</volume><issue>22</issue><spage>1</spage><epage>11</epage><pages>1-11</pages><issn>0027-8424</issn><issn>1091-6490</issn><eissn>1091-6490</eissn><abstract>Nonresolving inflammation underlies a range of chronic inflammatory diseases, and therapeutic acceleration of resolution of inflammation may improve outcomes. Neural reflexes regulate the intensity of inflammation (for example, through signals in the vagus nerve), but whether activation of the vagus nerve promotes the resolution of inflammation in vivo has been unknown. To investigate this, mice were subjected to electrical vagus nerve stimulation (VNS) or sham surgery at the cervical level followed by zymosan-induced peritonitis. The duration of inflammation resolution was significantly reduced and efferocytosis was significantly increased in mice treated with VNS as compared with sham. Lipid mediator (LM) metabololipidomics revealed that mice treated with VNS had higher levels of specialized proresolving mediators (SPMs), particularly from the omega-3 docosahexaenoic (DHA) and docosapentaenoic (n-3 DPA) metabolomes, in peritoneal exudates. VNS also shifted the ratio between proinflammatory and proresolving LMs toward a proresolving profile, but this effect by VNS was inverted in mice deficient in 12/15-lipoxgenase (Alox15), a key enzyme in this SPM biosynthesis. The significant VNS-mediated reduction of neutrophil numbers in peritoneal exudates was absent in mice deficient in the cholinergic α7-nicotinic acetylcholine receptor subunit (α7nAChR), an essential component of the inflammatory reflex. Thus, VNS increased local levels of SPM and accelerated resolution of inflammation in zymosan-induced peritonitis by a mechanism that involves Alox15 and requires the α7nAChR.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>35622894</pmid><doi>10.1073/pnas.2023285119</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0001-6328-3640</orcidid><orcidid>https://orcid.org/0000-0001-7723-9579</orcidid><orcidid>https://orcid.org/0000-0002-5163-3946</orcidid><orcidid>https://orcid.org/0000-0002-0127-8309</orcidid><orcidid>https://orcid.org/0000-0001-9210-121X</orcidid><orcidid>https://orcid.org/0000-0003-3473-5948</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0027-8424 |
| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2022-05, Vol.119 (22), p.1-11 |
| issn | 0027-8424 1091-6490 1091-6490 |
| language | eng |
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| source | MEDLINE; PubMed Central; Alma/SFX Local Collection; SWEPUB Freely available online; Free Full-Text Journals in Chemistry |
| subjects | a7nAChR gene Alox15 gene Alox15 protein alpha7 Nicotinic Acetylcholine Receptor alpha7 Nicotinic Acetylcholine Receptor - genetics animal animal cell animal experiment animal model animal tissue Animals Arachidonate 12-Lipoxygenase Arachidonate 12-Lipoxygenase - genetics Arachidonate 12-Lipoxygenase - metabolism Arachidonate 15-Lipoxygenase Arachidonate 15-Lipoxygenase - genetics Arachidonate 15-Lipoxygenase - metabolism autacoid autonomic reflex Biological Sciences Biosynthesis bungarotoxin receptor cervonic acid Cholinergics controlled study disease duration Disease Models, Animal docosapentaenoic acid efferocytosis ex vivo study Exudates Exudation gene genetics In vivo methods and tests in vivo study Inflammation Inflammation - therapy Inflammation Mediators Inflammation Mediators - metabolism Inflammatory diseases Leukocytes (neutrophilic) lipid mediators lipidomics Lipids male Mice Mice, Mutant Strains mouse Nerves nervous system inflammation neuroinflammation nonhuman Peritoneum peritoneum exudate Peritonitis physiology Reflexes Stimulation surgical technique Vagus Nerve Vagus Nerve - physiology Vagus Nerve Stimulation zymosan |
| title | Vagus nerve stimulation promotes resolution of inflammation by a mechanism that involves Alox15 and requires the α7nAChR subunit |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T05%3A29%3A49IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-jstor_swepu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Vagus%20nerve%20stimulation%20promotes%20resolution%20of%20inflammation%20by%20a%20mechanism%20that%20involves%20Alox15%20and%20requires%20the%20%CE%B17nAChR%20subunit&rft.jtitle=Proceedings%20of%20the%20National%20Academy%20of%20Sciences%20-%20PNAS&rft.au=Caravaca,%20April%20S.&rft.date=2022-05-31&rft.volume=119&rft.issue=22&rft.spage=1&rft.epage=11&rft.pages=1-11&rft.issn=0027-8424&rft.eissn=1091-6490&rft_id=info:doi/10.1073/pnas.2023285119&rft_dat=%3Cjstor_swepu%3E27152017%3C/jstor_swepu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2673629440&rft_id=info:pmid/35622894&rft_jstor_id=27152017&rfr_iscdi=true |