Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids
The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8 −/− mice spontaneously develop a lupus-like disease. Similar to...
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| Veröffentlicht in: | Cell death and differentiation 2013-09, Vol.20 (9), p.1230-1240 |
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| creator | Lauber, K Keppeler, H Munoz, L E Koppe, U Schröder, K Yamaguchi, H Krönke, G Uderhardt, S Wesselborg, S Belka, C Nagata, S Herrmann, M |
| description | The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8
−/−
mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs
in vitro
and
in vivo
. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE. |
| doi_str_mv | 10.1038/cdd.2013.82 |
| format | Article |
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−/−
mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs
in vitro
and
in vivo
. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/cdd.2013.82</identifier><identifier>PMID: 23832117</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/250/256 ; 631/80/313/1727 ; 631/80/82/23 ; 631/80/86 ; Animals ; Antigens, Surface - genetics ; Antigens, Surface - metabolism ; Apoptosis ; Apoptosis - immunology ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Cycle Analysis ; Cell death ; Cell Line, Tumor ; Cytokines ; Drug dosages ; Glucocorticoids - metabolism ; Humans ; Internal medicine ; Kinases ; Life Sciences ; Lupus ; Lupus Erythematosus, Systemic - genetics ; Lupus Erythematosus, Systemic - immunology ; Lupus Erythematosus, Systemic - metabolism ; Macrophages - immunology ; Medicine ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Milk ; Milk Proteins - genetics ; Milk Proteins - metabolism ; Oils & fats ; Oncology ; Opsonin Proteins - genetics ; Opsonin Proteins - metabolism ; Original Paper ; Phagocytosis - immunology ; Promoter Regions, Genetic ; Radiation ; Receptors, Glucocorticoid - metabolism ; Response Elements - genetics ; RNA Interference ; RNA, Small Interfering ; Stem Cells ; U937 Cells</subject><ispartof>Cell death and differentiation, 2013-09, Vol.20 (9), p.1230-1240</ispartof><rights>Macmillan Publishers Limited 2013</rights><rights>Copyright Nature Publishing Group Sep 2013</rights><rights>Copyright © 2013 Macmillan Publishers Limited 2013 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c512t-2f96dfdcb894a75fb0b33aaa6b20f6eaff9e27f4b4bb6dbbb6f28a5c1c9452103</citedby><cites>FETCH-LOGICAL-c512t-2f96dfdcb894a75fb0b33aaa6b20f6eaff9e27f4b4bb6dbbb6f28a5c1c9452103</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/PMC3741508/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741508/$$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/23832117$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lauber, K</creatorcontrib><creatorcontrib>Keppeler, H</creatorcontrib><creatorcontrib>Munoz, L E</creatorcontrib><creatorcontrib>Koppe, U</creatorcontrib><creatorcontrib>Schröder, K</creatorcontrib><creatorcontrib>Yamaguchi, H</creatorcontrib><creatorcontrib>Krönke, G</creatorcontrib><creatorcontrib>Uderhardt, S</creatorcontrib><creatorcontrib>Wesselborg, S</creatorcontrib><creatorcontrib>Belka, C</creatorcontrib><creatorcontrib>Nagata, S</creatorcontrib><creatorcontrib>Herrmann, M</creatorcontrib><title>Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8
−/−
mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs
in vitro
and
in vivo
. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE.</description><subject>631/250/256</subject><subject>631/80/313/1727</subject><subject>631/80/82/23</subject><subject>631/80/86</subject><subject>Animals</subject><subject>Antigens, Surface - genetics</subject><subject>Antigens, Surface - metabolism</subject><subject>Apoptosis</subject><subject>Apoptosis - immunology</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Cytokines</subject><subject>Drug dosages</subject><subject>Glucocorticoids - metabolism</subject><subject>Humans</subject><subject>Internal medicine</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Lupus</subject><subject>Lupus Erythematosus, Systemic - genetics</subject><subject>Lupus Erythematosus, Systemic - immunology</subject><subject>Lupus Erythematosus, Systemic - metabolism</subject><subject>Macrophages - immunology</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Milk</subject><subject>Milk Proteins - genetics</subject><subject>Milk Proteins - metabolism</subject><subject>Oils & fats</subject><subject>Oncology</subject><subject>Opsonin Proteins - genetics</subject><subject>Opsonin Proteins - metabolism</subject><subject>Original Paper</subject><subject>Phagocytosis - immunology</subject><subject>Promoter Regions, Genetic</subject><subject>Radiation</subject><subject>Receptors, Glucocorticoid - metabolism</subject><subject>Response Elements - genetics</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering</subject><subject>Stem Cells</subject><subject>U937 Cells</subject><issn>1350-9047</issn><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNptkc1rFTEUxYMotlZX7iXgRtB55muSmY0gpa1CxY2uQ5K5eW_qvMkzyQj9773Dq6WKm3xwfpycm0PIS842nMnufRiGjWBcbjrxiJxyZXTTKiYf41m2rOmZMifkWSk3jDFtev2UnAjZScG5OSXwZZx-0Ogq3U7JLxM0F1eXeA81ZdrRPQyjq1Bo3QGFeefmAHuYK02RukM61FTHQANMEw0TuLzq1N-i2RJSSBnVNA7lOXkS3VTgxd1-Rr5fXnw7_9Rcf736fP7xugktF7URsddDHILveuVMGz3zUjrntBcsanAx9iBMVF55rwePSxSdawMPvWoFfsYZ-XD0PSweowdMmt1kD3ncu3xrkxvt38o87uw2_bLSKN6yDg3e3Bnk9HOBUu1-LOt4boa0FMsV_rRWWnNEX_-D3qQlzzgeUryXrTFyTfT2SIWcSskQ78NwZtf6LNZn1_psJ5B-9TD_PfunLwTeHYGC0ryF_ODR__j9BoOKpnQ</recordid><startdate>20130901</startdate><enddate>20130901</enddate><creator>Lauber, K</creator><creator>Keppeler, H</creator><creator>Munoz, L E</creator><creator>Koppe, U</creator><creator>Schröder, K</creator><creator>Yamaguchi, H</creator><creator>Krönke, G</creator><creator>Uderhardt, S</creator><creator>Wesselborg, S</creator><creator>Belka, C</creator><creator>Nagata, S</creator><creator>Herrmann, M</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</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>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130901</creationdate><title>Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids</title><author>Lauber, K ; Keppeler, H ; Munoz, L E ; Koppe, U ; Schröder, K ; Yamaguchi, H ; Krönke, G ; Uderhardt, S ; Wesselborg, S ; Belka, C ; Nagata, S ; Herrmann, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c512t-2f96dfdcb894a75fb0b33aaa6b20f6eaff9e27f4b4bb6dbbb6f28a5c1c9452103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/250/256</topic><topic>631/80/313/1727</topic><topic>631/80/82/23</topic><topic>631/80/86</topic><topic>Animals</topic><topic>Antigens, Surface - genetics</topic><topic>Antigens, Surface - metabolism</topic><topic>Apoptosis</topic><topic>Apoptosis - immunology</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cell Biology</topic><topic>Cell Cycle Analysis</topic><topic>Cell death</topic><topic>Cell Line, Tumor</topic><topic>Cytokines</topic><topic>Drug dosages</topic><topic>Glucocorticoids - metabolism</topic><topic>Humans</topic><topic>Internal medicine</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Lupus</topic><topic>Lupus Erythematosus, Systemic - genetics</topic><topic>Lupus Erythematosus, Systemic - immunology</topic><topic>Lupus Erythematosus, Systemic - metabolism</topic><topic>Macrophages - immunology</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Milk</topic><topic>Milk Proteins - genetics</topic><topic>Milk Proteins - metabolism</topic><topic>Oils & fats</topic><topic>Oncology</topic><topic>Opsonin Proteins - genetics</topic><topic>Opsonin Proteins - metabolism</topic><topic>Original Paper</topic><topic>Phagocytosis - immunology</topic><topic>Promoter Regions, Genetic</topic><topic>Radiation</topic><topic>Receptors, Glucocorticoid - metabolism</topic><topic>Response Elements - genetics</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering</topic><topic>Stem Cells</topic><topic>U937 Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lauber, K</creatorcontrib><creatorcontrib>Keppeler, H</creatorcontrib><creatorcontrib>Munoz, L E</creatorcontrib><creatorcontrib>Koppe, U</creatorcontrib><creatorcontrib>Schröder, K</creatorcontrib><creatorcontrib>Yamaguchi, H</creatorcontrib><creatorcontrib>Krönke, G</creatorcontrib><creatorcontrib>Uderhardt, S</creatorcontrib><creatorcontrib>Wesselborg, S</creatorcontrib><creatorcontrib>Belka, C</creatorcontrib><creatorcontrib>Nagata, S</creatorcontrib><creatorcontrib>Herrmann, M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Proquest Health & Medical Complete</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</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)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</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>PML(ProQuest Medical Library)</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lauber, K</au><au>Keppeler, H</au><au>Munoz, L E</au><au>Koppe, U</au><au>Schröder, K</au><au>Yamaguchi, H</au><au>Krönke, G</au><au>Uderhardt, S</au><au>Wesselborg, S</au><au>Belka, C</au><au>Nagata, S</au><au>Herrmann, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2013-09-01</date><risdate>2013</risdate><volume>20</volume><issue>9</issue><spage>1230</spage><epage>1240</epage><pages>1230-1240</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>The phagocytic clearance of apoptotic cells is essential to prevent chronic inflammation and autoimmunity. The phosphatidylserine-binding protein milk fat globule-EGF factor 8 (MFG-E8) is a major opsonin for apoptotic cells, and MFG-E8
−/−
mice spontaneously develop a lupus-like disease. Similar to human systemic lupus erythematosus (SLE), the murine disease is associated with an impaired clearance of apoptotic cells. SLE is routinely treated with glucocorticoids (GCs), whose anti-inflammatory effects are consentaneously attributed to the transrepression of pro-inflammatory cytokines. Here, we show that the GC-mediated transactivation of MFG-E8 expression and the concomitantly enhanced elimination of apoptotic cells constitute a novel aspect in this context. Patients with chronic inflammation receiving high-dose prednisone therapy displayed substantially increased MFG-E8 mRNA levels in circulating monocytes. MFG-E8 induction was dependent on the GC receptor and several GC response elements within the MFG-E8 promoter. Most intriguingly, the inhibition of MFG-E8 induction by RNA interference or genetic knockout strongly reduced or completely abolished the phagocytosis-enhancing effect of GCs
in vitro
and
in vivo
. Thus, MFG-E8-dependent promotion of apoptotic cell clearance is a novel anti-inflammatory facet of GC treatment and renders MFG-E8 a prospective target for future therapeutic interventions in SLE.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23832117</pmid><doi>10.1038/cdd.2013.82</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell death and differentiation, 2013-09, Vol.20 (9), p.1230-1240 |
| issn | 1350-9047 1476-5403 |
| language | eng |
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| source | MEDLINE; Free E-Journal (出版社公開部分のみ）; PubMed Central; Alma/SFX Local Collection |
| subjects | 631/250/256 631/80/313/1727 631/80/82/23 631/80/86 Animals Antigens, Surface - genetics Antigens, Surface - metabolism Apoptosis Apoptosis - immunology Biochemistry Biomedical and Life Sciences Cell Biology Cell Cycle Analysis Cell death Cell Line, Tumor Cytokines Drug dosages Glucocorticoids - metabolism Humans Internal medicine Kinases Life Sciences Lupus Lupus Erythematosus, Systemic - genetics Lupus Erythematosus, Systemic - immunology Lupus Erythematosus, Systemic - metabolism Macrophages - immunology Medicine Mice Mice, Inbred C57BL Mice, Knockout Milk Milk Proteins - genetics Milk Proteins - metabolism Oils & fats Oncology Opsonin Proteins - genetics Opsonin Proteins - metabolism Original Paper Phagocytosis - immunology Promoter Regions, Genetic Radiation Receptors, Glucocorticoid - metabolism Response Elements - genetics RNA Interference RNA, Small Interfering Stem Cells U937 Cells |
| title | Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids |
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