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Hyperglycemia acts in synergy with hypoxia to maintain the pro-inflammatory phenotype of macrophages
Diabetic foot ulcers (DFUs) are characterized by a chronic inflammation state which prevents cutaneous wound healing, and DFUs eventually lead to infection and leg amputation. Macrophages located in DFUs are locked in an pro-inflammatory phenotype. In this study, the effect of hyperglycemia and hypo...
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| Published in: | PloS one 2019-08, Vol.14 (8), p.e0220577-e0220577 |
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| creator | Morey, Mangesh O'Gaora, Peadar Pandit, Abhay Hélary, Christophe |
| description | Diabetic foot ulcers (DFUs) are characterized by a chronic inflammation state which prevents cutaneous wound healing, and DFUs eventually lead to infection and leg amputation. Macrophages located in DFUs are locked in an pro-inflammatory phenotype. In this study, the effect of hyperglycemia and hypoxia on the macrophage phenotype was analyzed. For this purpose, a microarray was performed to study the gene expression profile of macrophages cultivated in a high glucose concentration. Hyperglycemia upregulated the expression of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, chemokines and downregulated the expression of two receptors involved in phagocytosis (CD 36 and Class B scavenger type I receptors). In addition, eleven anti-apoptotic factors were upregulated whereas three pro-apoptotic genes were downregulated. Subsequently, the contribution of hypoxia and hyperglycemia to chronic inflammation and their potential synergistic effect was evaluated on activated THP-1 derived macrophages. A long term post activation effect (17 hours) was only observed on the upregulation of pro-inflammatory cytokines when hypoxia was combined with a high glucose concentration. In contrast, hyperglycemia and hypoxia did not have any effect on wound healing molecules such as TGF-β1. Taken together, the results show that hyperglycemia acts in synergy with hypoxia to maintain a chronic inflammation state in macrophages. |
| doi_str_mv | 10.1371/journal.pone.0220577 |
| format | article |
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Macrophages located in DFUs are locked in an pro-inflammatory phenotype. In this study, the effect of hyperglycemia and hypoxia on the macrophage phenotype was analyzed. For this purpose, a microarray was performed to study the gene expression profile of macrophages cultivated in a high glucose concentration. Hyperglycemia upregulated the expression of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, chemokines and downregulated the expression of two receptors involved in phagocytosis (CD 36 and Class B scavenger type I receptors). In addition, eleven anti-apoptotic factors were upregulated whereas three pro-apoptotic genes were downregulated. Subsequently, the contribution of hypoxia and hyperglycemia to chronic inflammation and their potential synergistic effect was evaluated on activated THP-1 derived macrophages. A long term post activation effect (17 hours) was only observed on the upregulation of pro-inflammatory cytokines when hypoxia was combined with a high glucose concentration. In contrast, hyperglycemia and hypoxia did not have any effect on wound healing molecules such as TGF-β1. Taken together, the results show that hyperglycemia acts in synergy with hypoxia to maintain a chronic inflammation state in macrophages.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0220577</identifier><identifier>PMID: 31415598</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amputation ; Angiogenesis ; Anopheles ; Anoxia ; Apoptosis ; Apoptosis - physiology ; Biochemistry ; Biology and Life Sciences ; Bone morphogenetic proteins ; Cell activation ; Cell Differentiation - drug effects ; Cell Hypoxia - physiology ; Cell Line, Tumor ; Chemokines ; Complications and side effects ; Cytokines ; Cytokines - metabolism ; Diabetes ; Diabetes mellitus ; Diabetic foot ; Diabetic Foot - metabolism ; DNA microarrays ; Endocrinology and metabolism ; Foot diseases ; Gene expression ; Genes ; Genetic aspects ; Genotype & phenotype ; Glucose ; Glucose - administration & dosage ; Human health and pathology ; Humans ; Hyperglycemia ; Hyperglycemia - metabolism ; Hypoxia ; Infection ; Inflammation ; Interleukin 1 ; Interleukin 6 ; Interleukin-6 - metabolism ; Leg ulcers ; Life Sciences ; Macrophages ; Macrophages - drug effects ; Macrophages - metabolism ; Medical equipment ; Medicine and Health Sciences ; Neutrophils ; Phagocytosis ; Phenotypes ; Physical Sciences ; Receptors ; Risk factors ; Synergistic effect ; Transforming growth factor-b1 ; Transforming growth factors ; Tumor necrosis factor ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-α ; Ulcers ; Up-Regulation - drug effects ; Wound care ; Wound healing ; Wound Healing - physiology</subject><ispartof>PloS one, 2019-08, Vol.14 (8), p.e0220577-e0220577</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Morey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>2019 Morey et al 2019 Morey et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c726t-8040f2a3087657e5d6312925eabb34e5388344efa6f49c7eb505acbe6ffbe8b43</citedby><cites>FETCH-LOGICAL-c726t-8040f2a3087657e5d6312925eabb34e5388344efa6f49c7eb505acbe6ffbe8b43</cites><orcidid>0000-0002-6292-4933 ; 0000-0001-9312-7278</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2273747788/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2273747788?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31415598$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.sorbonne-universite.fr/hal-02302288$$DView record in HAL$$Hfree_for_read</backlink></links><search><contributor>Mukhopadhyay, Partha</contributor><creatorcontrib>Morey, Mangesh</creatorcontrib><creatorcontrib>O'Gaora, Peadar</creatorcontrib><creatorcontrib>Pandit, Abhay</creatorcontrib><creatorcontrib>Hélary, Christophe</creatorcontrib><title>Hyperglycemia acts in synergy with hypoxia to maintain the pro-inflammatory phenotype of macrophages</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Diabetic foot ulcers (DFUs) are characterized by a chronic inflammation state which prevents cutaneous wound healing, and DFUs eventually lead to infection and leg amputation. Macrophages located in DFUs are locked in an pro-inflammatory phenotype. In this study, the effect of hyperglycemia and hypoxia on the macrophage phenotype was analyzed. For this purpose, a microarray was performed to study the gene expression profile of macrophages cultivated in a high glucose concentration. Hyperglycemia upregulated the expression of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, chemokines and downregulated the expression of two receptors involved in phagocytosis (CD 36 and Class B scavenger type I receptors). In addition, eleven anti-apoptotic factors were upregulated whereas three pro-apoptotic genes were downregulated. Subsequently, the contribution of hypoxia and hyperglycemia to chronic inflammation and their potential synergistic effect was evaluated on activated THP-1 derived macrophages. A long term post activation effect (17 hours) was only observed on the upregulation of pro-inflammatory cytokines when hypoxia was combined with a high glucose concentration. In contrast, hyperglycemia and hypoxia did not have any effect on wound healing molecules such as TGF-β1. Taken together, the results show that hyperglycemia acts in synergy with hypoxia to maintain a chronic inflammation state in macrophages.</description><subject>Amputation</subject><subject>Angiogenesis</subject><subject>Anopheles</subject><subject>Anoxia</subject><subject>Apoptosis</subject><subject>Apoptosis - physiology</subject><subject>Biochemistry</subject><subject>Biology and Life Sciences</subject><subject>Bone morphogenetic proteins</subject><subject>Cell activation</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Hypoxia - physiology</subject><subject>Cell Line, Tumor</subject><subject>Chemokines</subject><subject>Complications and side effects</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Diabetic foot</subject><subject>Diabetic Foot - metabolism</subject><subject>DNA microarrays</subject><subject>Endocrinology and metabolism</subject><subject>Foot diseases</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genotype & phenotype</subject><subject>Glucose</subject><subject>Glucose - administration & dosage</subject><subject>Human health and pathology</subject><subject>Humans</subject><subject>Hyperglycemia</subject><subject>Hyperglycemia - metabolism</subject><subject>Hypoxia</subject><subject>Infection</subject><subject>Inflammation</subject><subject>Interleukin 1</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - metabolism</subject><subject>Leg ulcers</subject><subject>Life Sciences</subject><subject>Macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - metabolism</subject><subject>Medical equipment</subject><subject>Medicine and Health Sciences</subject><subject>Neutrophils</subject><subject>Phagocytosis</subject><subject>Phenotypes</subject><subject>Physical Sciences</subject><subject>Receptors</subject><subject>Risk factors</subject><subject>Synergistic effect</subject><subject>Transforming growth factor-b1</subject><subject>Transforming growth factors</subject><subject>Tumor necrosis factor</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><subject>Ulcers</subject><subject>Up-Regulation - drug effects</subject><subject>Wound care</subject><subject>Wound healing</subject><subject>Wound Healing - physiology</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11r2zAUhs3YWLts_2BshsFYL5LJ-rRvBqFsSyBQ2NetkG3ZVrAt15K7-t_vpHFLXHoxjLE5et5XR-foBMHbCK0iIqLPezv0rapXnW31CmGMmBDPgvMoIXjJMSLPT_7PglfO7RFiJOb8ZXBGIhoxlsTnQb4ZO92X9ZjpxqhQZd6Fpg3d2EJ0DP8aX4XV2NlbWPQ2bJRpPbyhr3TY9XZp2qJWTaO87cewq3RrPRiGtgA0621XqVK718GLQtVOv5m-i-D3t6-_LjfL3dX37eV6t8wE5n4ZI4oKrAiKBWdCs5yTCCeYaZWmhGpIPiaU6kLxgiaZ0ClDTGWp5kWR6jilZBG8P_p2tXVyKpCTGAsiqBAgXwTbI5FbtZddbxrVj9IqI-8Cti-l6r3Jai0jlookzhXNRUEZjZVAcZrrKKOUc0oFeH2ZdhvSRueZbn2v6pnpfKU1lSztjeQ8YRFnYHBxNKgeyTbrnTzEECbQ2Di-iYD9NG3W2-tBOy8b4zJd16rVdrg7I8OQJbR8EXx4hD5diYkqFRwW2mghx-xgKtcs4WAmBAZq9QQFTw7XJYObVxiIzwQXMwEwXt_6Ug3Oye3PH__PXv2Zsx9P2Eqr2lfO1oM3tnVzkB5BuH3O9bp4qGyE5GFw7qshD4Mjp8EB2bvTZj6I7ieF_AN8qRNF</recordid><startdate>20190815</startdate><enddate>20190815</enddate><creator>Morey, Mangesh</creator><creator>O'Gaora, Peadar</creator><creator>Pandit, Abhay</creator><creator>Hélary, Christophe</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>1XC</scope><scope>VOOES</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-6292-4933</orcidid><orcidid>https://orcid.org/0000-0001-9312-7278</orcidid></search><sort><creationdate>20190815</creationdate><title>Hyperglycemia acts in synergy with hypoxia to maintain the pro-inflammatory phenotype of macrophages</title><author>Morey, Mangesh ; O'Gaora, Peadar ; Pandit, Abhay ; Hélary, Christophe</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c726t-8040f2a3087657e5d6312925eabb34e5388344efa6f49c7eb505acbe6ffbe8b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Amputation</topic><topic>Angiogenesis</topic><topic>Anopheles</topic><topic>Anoxia</topic><topic>Apoptosis</topic><topic>Apoptosis - physiology</topic><topic>Biochemistry</topic><topic>Biology and Life Sciences</topic><topic>Bone morphogenetic proteins</topic><topic>Cell activation</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Hypoxia - physiology</topic><topic>Cell Line, Tumor</topic><topic>Chemokines</topic><topic>Complications and side effects</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Diabetic foot</topic><topic>Diabetic Foot - metabolism</topic><topic>DNA microarrays</topic><topic>Endocrinology and metabolism</topic><topic>Foot diseases</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genotype & phenotype</topic><topic>Glucose</topic><topic>Glucose - administration & dosage</topic><topic>Human health and pathology</topic><topic>Humans</topic><topic>Hyperglycemia</topic><topic>Hyperglycemia - metabolism</topic><topic>Hypoxia</topic><topic>Infection</topic><topic>Inflammation</topic><topic>Interleukin 1</topic><topic>Interleukin 6</topic><topic>Interleukin-6 - 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Macrophages located in DFUs are locked in an pro-inflammatory phenotype. In this study, the effect of hyperglycemia and hypoxia on the macrophage phenotype was analyzed. For this purpose, a microarray was performed to study the gene expression profile of macrophages cultivated in a high glucose concentration. Hyperglycemia upregulated the expression of pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, chemokines and downregulated the expression of two receptors involved in phagocytosis (CD 36 and Class B scavenger type I receptors). In addition, eleven anti-apoptotic factors were upregulated whereas three pro-apoptotic genes were downregulated. Subsequently, the contribution of hypoxia and hyperglycemia to chronic inflammation and their potential synergistic effect was evaluated on activated THP-1 derived macrophages. A long term post activation effect (17 hours) was only observed on the upregulation of pro-inflammatory cytokines when hypoxia was combined with a high glucose concentration. In contrast, hyperglycemia and hypoxia did not have any effect on wound healing molecules such as TGF-β1. Taken together, the results show that hyperglycemia acts in synergy with hypoxia to maintain a chronic inflammation state in macrophages.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31415598</pmid><doi>10.1371/journal.pone.0220577</doi><tpages>e0220577</tpages><orcidid>https://orcid.org/0000-0002-6292-4933</orcidid><orcidid>https://orcid.org/0000-0001-9312-7278</orcidid><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-08, Vol.14 (8), p.e0220577-e0220577 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2273747788 |
| source | Publicly Available Content Database; PubMed Central |
| subjects | Amputation Angiogenesis Anopheles Anoxia Apoptosis Apoptosis - physiology Biochemistry Biology and Life Sciences Bone morphogenetic proteins Cell activation Cell Differentiation - drug effects Cell Hypoxia - physiology Cell Line, Tumor Chemokines Complications and side effects Cytokines Cytokines - metabolism Diabetes Diabetes mellitus Diabetic foot Diabetic Foot - metabolism DNA microarrays Endocrinology and metabolism Foot diseases Gene expression Genes Genetic aspects Genotype & phenotype Glucose Glucose - administration & dosage Human health and pathology Humans Hyperglycemia Hyperglycemia - metabolism Hypoxia Infection Inflammation Interleukin 1 Interleukin 6 Interleukin-6 - metabolism Leg ulcers Life Sciences Macrophages Macrophages - drug effects Macrophages - metabolism Medical equipment Medicine and Health Sciences Neutrophils Phagocytosis Phenotypes Physical Sciences Receptors Risk factors Synergistic effect Transforming growth factor-b1 Transforming growth factors Tumor necrosis factor Tumor Necrosis Factor-alpha - metabolism Tumor necrosis factor-α Ulcers Up-Regulation - drug effects Wound care Wound healing Wound Healing - physiology |
| title | Hyperglycemia acts in synergy with hypoxia to maintain the pro-inflammatory phenotype of macrophages |
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