GnRH impairs diabetic wound healing through enhanced NETosis
It has been reported that neutrophil extracellular traps (NETs) impair wound healing in diabetes and that inhibiting NET generation (NETosis) improves wound healing in diabetic mice. Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of G...
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| Veröffentlicht in: | Cellular & molecular immunology 2020-08, Vol.17 (8), p.856-864 |
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| creator | Lee, Yun Sang Kang, Sung Un Lee, Myung-Hoon Kim, Haeng-Jun Han, Chang-Hak Won, Ho-Ryun Park, Young Uk Kim, Chul-Ho |
| description | It has been reported that neutrophil extracellular traps (NETs) impair wound healing in diabetes and that inhibiting NET generation (NETosis) improves wound healing in diabetic mice. Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of GnRH in diabetic wound healing is unclear. We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing. A mouse model of diabetes was established using five injections with streptozotocin. Mice with blood glucose levels >250 mg/dL were then used in the experiments. GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice. In contrast, GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing. The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients. In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate (PMA)-induced NETosis in mouse and human neutrophils. Furthermore, GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis, which were increased by GnRH treatment. These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds. Thus, inhibition of GnRH might be a novel treatment of diabetic foot ulcers. |
| doi_str_mv | 10.1038/s41423-019-0252-y |
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Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of GnRH in diabetic wound healing is unclear. We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing. A mouse model of diabetes was established using five injections with streptozotocin. Mice with blood glucose levels >250 mg/dL were then used in the experiments. GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice. In contrast, GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing. The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients. In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate (PMA)-induced NETosis in mouse and human neutrophils. Furthermore, GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis, which were increased by GnRH treatment. These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds. Thus, inhibition of GnRH might be a novel treatment of diabetic foot ulcers.</description><identifier>ISSN: 1672-7681</identifier><identifier>EISSN: 2042-0226</identifier><identifier>DOI: 10.1038/s41423-019-0252-y</identifier><identifier>PMID: 31217526</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>12-O-Tetradecanoylphorbol-13-acetate ; 631/250/1932 ; 631/250/2504/223/1699 ; Acetic acid ; Agonists ; Antibodies ; Biomedical and Life Sciences ; Biomedicine ; Citrulline ; Diabetes ; Diabetes mellitus ; Gonadotropin-releasing hormone ; Gonadotropins ; Histone H3 ; Immunology ; Leukocytes (neutrophilic) ; Medical Microbiology ; Microbiology ; Neutrophils ; Pituitary (anterior) ; Skin ; Streptozocin ; Ulcers ; Vaccine ; Wound healing</subject><ispartof>Cellular & molecular immunology, 2020-08, Vol.17 (8), p.856-864</ispartof><rights>The Author(s) 2019</rights><rights>The Author(s) 2019.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-cba6d8747897709f361a8b3e0597f0d90534698f5d2baa1cba7eb93865ced663</citedby><cites>FETCH-LOGICAL-c470t-cba6d8747897709f361a8b3e0597f0d90534698f5d2baa1cba7eb93865ced663</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395134/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395134/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31217526$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Yun Sang</creatorcontrib><creatorcontrib>Kang, Sung Un</creatorcontrib><creatorcontrib>Lee, Myung-Hoon</creatorcontrib><creatorcontrib>Kim, Haeng-Jun</creatorcontrib><creatorcontrib>Han, Chang-Hak</creatorcontrib><creatorcontrib>Won, Ho-Ryun</creatorcontrib><creatorcontrib>Park, Young Uk</creatorcontrib><creatorcontrib>Kim, Chul-Ho</creatorcontrib><title>GnRH impairs diabetic wound healing through enhanced NETosis</title><title>Cellular & molecular immunology</title><addtitle>Cell Mol Immunol</addtitle><addtitle>Cell Mol Immunol</addtitle><description>It has been reported that neutrophil extracellular traps (NETs) impair wound healing in diabetes and that inhibiting NET generation (NETosis) improves wound healing in diabetic mice. Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of GnRH in diabetic wound healing is unclear. We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing. A mouse model of diabetes was established using five injections with streptozotocin. Mice with blood glucose levels >250 mg/dL were then used in the experiments. GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice. In contrast, GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing. The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients. In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate (PMA)-induced NETosis in mouse and human neutrophils. Furthermore, GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis, which were increased by GnRH treatment. These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds. Thus, inhibition of GnRH might be a novel treatment of diabetic foot ulcers.</description><subject>12-O-Tetradecanoylphorbol-13-acetate</subject><subject>631/250/1932</subject><subject>631/250/2504/223/1699</subject><subject>Acetic acid</subject><subject>Agonists</subject><subject>Antibodies</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Citrulline</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Gonadotropin-releasing hormone</subject><subject>Gonadotropins</subject><subject>Histone H3</subject><subject>Immunology</subject><subject>Leukocytes (neutrophilic)</subject><subject>Medical Microbiology</subject><subject>Microbiology</subject><subject>Neutrophils</subject><subject>Pituitary (anterior)</subject><subject>Skin</subject><subject>Streptozocin</subject><subject>Ulcers</subject><subject>Vaccine</subject><subject>Wound healing</subject><issn>1672-7681</issn><issn>2042-0226</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kctKxDAUhoMoOl4ewI0U3Lip5takARFEdBREQWYf0jZtI20yJq0yb2-GGccLuArhfOc_OfkAOEbwHEGSXwSKKCYpRCKFOMPpYgtMMKQ43jDbBhPEOE45y9Ee2A_hFcIsp5zugj2CMOIZZhNwObUv94np58r4kFRGFXowZfLhRlslrVadsU0ytN6NTZto2ypb6ip5up25YMIh2KlVF_TR-jwAs7vb2c19-vg8fbi5fkxLyuGQloViVc4pzwXnUNSEIZUXRMNM8BpWAmaEMpHXWYULpVDEuS4EyVkWZzFGDsDVKnY-Fr2uSm0Hrzo596ZXfiGdMvJ3xZpWNu5dciIyRGgMOFsHePc26jDI3oRSd52y2o1BYkwpIpBjEtHTP-irG72N20lMsSBUxK-LFFpRpXcheF1vHoOgXKqRKzUyqpFLNXIRe05-brHp-HIRAbwCQizZRvvv0f-nfgJ9IJlx</recordid><startdate>20200801</startdate><enddate>20200801</enddate><creator>Lee, Yun Sang</creator><creator>Kang, Sung Un</creator><creator>Lee, Myung-Hoon</creator><creator>Kim, Haeng-Jun</creator><creator>Han, Chang-Hak</creator><creator>Won, Ho-Ryun</creator><creator>Park, Young Uk</creator><creator>Kim, Chul-Ho</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20200801</creationdate><title>GnRH impairs diabetic wound healing through enhanced NETosis</title><author>Lee, Yun Sang ; Kang, Sung Un ; Lee, Myung-Hoon ; Kim, Haeng-Jun ; Han, Chang-Hak ; Won, Ho-Ryun ; Park, Young Uk ; Kim, Chul-Ho</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-cba6d8747897709f361a8b3e0597f0d90534698f5d2baa1cba7eb93865ced663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>12-O-Tetradecanoylphorbol-13-acetate</topic><topic>631/250/1932</topic><topic>631/250/2504/223/1699</topic><topic>Acetic acid</topic><topic>Agonists</topic><topic>Antibodies</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Citrulline</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Gonadotropin-releasing hormone</topic><topic>Gonadotropins</topic><topic>Histone H3</topic><topic>Immunology</topic><topic>Leukocytes (neutrophilic)</topic><topic>Medical Microbiology</topic><topic>Microbiology</topic><topic>Neutrophils</topic><topic>Pituitary (anterior)</topic><topic>Skin</topic><topic>Streptozocin</topic><topic>Ulcers</topic><topic>Vaccine</topic><topic>Wound healing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Yun Sang</creatorcontrib><creatorcontrib>Kang, Sung Un</creatorcontrib><creatorcontrib>Lee, Myung-Hoon</creatorcontrib><creatorcontrib>Kim, Haeng-Jun</creatorcontrib><creatorcontrib>Han, Chang-Hak</creatorcontrib><creatorcontrib>Won, Ho-Ryun</creatorcontrib><creatorcontrib>Park, Young Uk</creatorcontrib><creatorcontrib>Kim, Chul-Ho</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cellular & molecular immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Yun Sang</au><au>Kang, Sung Un</au><au>Lee, Myung-Hoon</au><au>Kim, Haeng-Jun</au><au>Han, Chang-Hak</au><au>Won, Ho-Ryun</au><au>Park, Young Uk</au><au>Kim, Chul-Ho</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>GnRH impairs diabetic wound healing through enhanced NETosis</atitle><jtitle>Cellular & molecular immunology</jtitle><stitle>Cell Mol Immunol</stitle><addtitle>Cell Mol Immunol</addtitle><date>2020-08-01</date><risdate>2020</risdate><volume>17</volume><issue>8</issue><spage>856</spage><epage>864</epage><pages>856-864</pages><issn>1672-7681</issn><eissn>2042-0226</eissn><abstract>It has been reported that neutrophil extracellular traps (NETs) impair wound healing in diabetes and that inhibiting NET generation (NETosis) improves wound healing in diabetic mice. Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of GnRH in diabetic wound healing is unclear. We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing. A mouse model of diabetes was established using five injections with streptozotocin. Mice with blood glucose levels >250 mg/dL were then used in the experiments. GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice. In contrast, GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing. The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients. In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate (PMA)-induced NETosis in mouse and human neutrophils. Furthermore, GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis, which were increased by GnRH treatment. These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds. Thus, inhibition of GnRH might be a novel treatment of diabetic foot ulcers.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31217526</pmid><doi>10.1038/s41423-019-0252-y</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 12-O-Tetradecanoylphorbol-13-acetate 631/250/1932 631/250/2504/223/1699 Acetic acid Agonists Antibodies Biomedical and Life Sciences Biomedicine Citrulline Diabetes Diabetes mellitus Gonadotropin-releasing hormone Gonadotropins Histone H3 Immunology Leukocytes (neutrophilic) Medical Microbiology Microbiology Neutrophils Pituitary (anterior) Skin Streptozocin Ulcers Vaccine Wound healing |
| title | GnRH impairs diabetic wound healing through enhanced NETosis |
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