Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage
Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on...
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| creator | Huang, Wei Wu, Jiyuan Yang, Huiqin Xiong, Yin Jiang, Rui Cui, Tianpen Ye, Duyun |
| description | Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of MFG-E8 leads to uncontrolled early pulmonary and peritoneal inflammation and tissue damage in mice with pristane-induced lupus. Consistent with these findings, MFG-E8-deficient mice that are exposed to pristane show enhanced neutrophil accumulation and increased neutrophil death, including apoptosis, necrosis and NETosis, as well as impaired phagocytosis of macrophages. The consequences are the expansion of diffuse pulmonary hemorrhage, increased anti-nuclear antibody, anti-dsDNA antibody and anti-neutrophil cytoplasmic antibody levels, and enhanced immune complexes deposition and neutrophil extracellular traps (NETs) formation in the lung and kidney tissues of MFG-E8-deficient mice exposed to pristane. In patients with SLE and mice with pristane-induced lupus, neutrophil accumulation is elevated, which depends on higher expression of the surface receptor CXCR2. After pretreatment with recombinant MFG-E8, the surface expression of CXCR2 on neutrophil is downregulated, and the MFG-E8 deletion increase CXCR2 expression by ~40%. These studies indicate that MFG-E8 reduces neutrophil migration and NETosis via downregulating surface CXCR2 expression in parallel with its role in the phagocytosis of apoptotic neutrophils, suggesting that MFG-E8 may serve as a therapeutic agent for attenuating the early inflammatory responses of SLE and protect patients from lupus-related damage. |
| doi_str_mv | 10.1038/cdd.2016.115 |
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In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of MFG-E8 leads to uncontrolled early pulmonary and peritoneal inflammation and tissue damage in mice with pristane-induced lupus. Consistent with these findings, MFG-E8-deficient mice that are exposed to pristane show enhanced neutrophil accumulation and increased neutrophil death, including apoptosis, necrosis and NETosis, as well as impaired phagocytosis of macrophages. The consequences are the expansion of diffuse pulmonary hemorrhage, increased anti-nuclear antibody, anti-dsDNA antibody and anti-neutrophil cytoplasmic antibody levels, and enhanced immune complexes deposition and neutrophil extracellular traps (NETs) formation in the lung and kidney tissues of MFG-E8-deficient mice exposed to pristane. In patients with SLE and mice with pristane-induced lupus, neutrophil accumulation is elevated, which depends on higher expression of the surface receptor CXCR2. After pretreatment with recombinant MFG-E8, the surface expression of CXCR2 on neutrophil is downregulated, and the MFG-E8 deletion increase CXCR2 expression by ~40%. These studies indicate that MFG-E8 reduces neutrophil migration and NETosis via downregulating surface CXCR2 expression in parallel with its role in the phagocytosis of apoptotic neutrophils, suggesting that MFG-E8 may serve as a therapeutic agent for attenuating the early inflammatory responses of SLE and protect patients from lupus-related damage.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/cdd.2016.115</identifier><identifier>PMID: 27768123</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 38/79 ; 631/250/1933 ; 692/420/2780 ; 96/31 ; 96/34 ; Adult ; Animals ; Antibodies ; Antigens ; Antigens, Surface - genetics ; Antigens, Surface - metabolism ; Apoptosis ; Apoptosis - drug effects ; Autoantibodies - blood ; Biochemistry ; Biomedical and Life Sciences ; Bronchoalveolar Lavage Fluid - chemistry ; Bronchoalveolar Lavage Fluid - cytology ; Cell Biology ; Cell Cycle Analysis ; Cell death ; Cytokines - analysis ; Disease Models, Animal ; Down-Regulation - drug effects ; Female ; Fullerenes ; Glomerulonephritis - pathology ; Granulocytes ; Hospitals ; Humans ; Immunology ; Kidney - metabolism ; Kinases ; Life Sciences ; Lung - metabolism ; Lupus ; Lupus Erythematosus, Systemic - chemically induced ; Lupus Erythematosus, Systemic - immunology ; Lupus Erythematosus, Systemic - pathology ; Medical schools ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Milk ; Milk Proteins - genetics ; Milk Proteins - metabolism ; Neutrophils ; Neutrophils - cytology ; Neutrophils - immunology ; Neutrophils - metabolism ; Oils & fats ; Original Paper ; Pathogenesis ; Pathophysiology ; Phagocytosis - drug effects ; Proteins ; Receptors, Interleukin-8B - metabolism ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - pharmacology ; Science ; Stem Cells ; Young Adult</subject><ispartof>Cell death and differentiation, 2017-02, Vol.24 (2), p.263-275</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Feb 2017</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-p295t-7fed8c56a9708c54d473a09017bc70a29b2ba77dbb4c234d01b10600789e074d3</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/PMC5299708/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299708/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27768123$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Wei</creatorcontrib><creatorcontrib>Wu, Jiyuan</creatorcontrib><creatorcontrib>Yang, Huiqin</creatorcontrib><creatorcontrib>Xiong, Yin</creatorcontrib><creatorcontrib>Jiang, Rui</creatorcontrib><creatorcontrib>Cui, Tianpen</creatorcontrib><creatorcontrib>Ye, Duyun</creatorcontrib><title>Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of MFG-E8 leads to uncontrolled early pulmonary and peritoneal inflammation and tissue damage in mice with pristane-induced lupus. Consistent with these findings, MFG-E8-deficient mice that are exposed to pristane show enhanced neutrophil accumulation and increased neutrophil death, including apoptosis, necrosis and NETosis, as well as impaired phagocytosis of macrophages. The consequences are the expansion of diffuse pulmonary hemorrhage, increased anti-nuclear antibody, anti-dsDNA antibody and anti-neutrophil cytoplasmic antibody levels, and enhanced immune complexes deposition and neutrophil extracellular traps (NETs) formation in the lung and kidney tissues of MFG-E8-deficient mice exposed to pristane. In patients with SLE and mice with pristane-induced lupus, neutrophil accumulation is elevated, which depends on higher expression of the surface receptor CXCR2. After pretreatment with recombinant MFG-E8, the surface expression of CXCR2 on neutrophil is downregulated, and the MFG-E8 deletion increase CXCR2 expression by ~40%. These studies indicate that MFG-E8 reduces neutrophil migration and NETosis via downregulating surface CXCR2 expression in parallel with its role in the phagocytosis of apoptotic neutrophils, suggesting that MFG-E8 may serve as a therapeutic agent for attenuating the early inflammatory responses of SLE and protect patients from lupus-related damage.</description><subject>13/1</subject><subject>38/79</subject><subject>631/250/1933</subject><subject>692/420/2780</subject><subject>96/31</subject><subject>96/34</subject><subject>Adult</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antigens</subject><subject>Antigens, Surface - genetics</subject><subject>Antigens, Surface - metabolism</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Autoantibodies - blood</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Bronchoalveolar Lavage Fluid - chemistry</subject><subject>Bronchoalveolar Lavage Fluid - cytology</subject><subject>Cell Biology</subject><subject>Cell Cycle Analysis</subject><subject>Cell death</subject><subject>Cytokines - analysis</subject><subject>Disease Models, Animal</subject><subject>Down-Regulation - drug effects</subject><subject>Female</subject><subject>Fullerenes</subject><subject>Glomerulonephritis - pathology</subject><subject>Granulocytes</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Immunology</subject><subject>Kidney - metabolism</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Lung - metabolism</subject><subject>Lupus</subject><subject>Lupus Erythematosus, Systemic - chemically induced</subject><subject>Lupus Erythematosus, Systemic - immunology</subject><subject>Lupus Erythematosus, Systemic - pathology</subject><subject>Medical schools</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Middle Aged</subject><subject>Milk</subject><subject>Milk Proteins - 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genetics</topic><topic>Antigens, Surface - metabolism</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Autoantibodies - blood</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Bronchoalveolar Lavage Fluid - chemistry</topic><topic>Bronchoalveolar Lavage Fluid - cytology</topic><topic>Cell Biology</topic><topic>Cell Cycle Analysis</topic><topic>Cell death</topic><topic>Cytokines - analysis</topic><topic>Disease Models, Animal</topic><topic>Down-Regulation - drug effects</topic><topic>Female</topic><topic>Fullerenes</topic><topic>Glomerulonephritis - pathology</topic><topic>Granulocytes</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Immunology</topic><topic>Kidney - metabolism</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Lung - metabolism</topic><topic>Lupus</topic><topic>Lupus Erythematosus, Systemic - chemically induced</topic><topic>Lupus Erythematosus, Systemic - immunology</topic><topic>Lupus Erythematosus, Systemic - pathology</topic><topic>Medical schools</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Middle Aged</topic><topic>Milk</topic><topic>Milk Proteins - genetics</topic><topic>Milk Proteins - metabolism</topic><topic>Neutrophils</topic><topic>Neutrophils - cytology</topic><topic>Neutrophils - immunology</topic><topic>Neutrophils - metabolism</topic><topic>Oils & fats</topic><topic>Original Paper</topic><topic>Pathogenesis</topic><topic>Pathophysiology</topic><topic>Phagocytosis - drug effects</topic><topic>Proteins</topic><topic>Receptors, Interleukin-8B - metabolism</topic><topic>Recombinant Proteins - biosynthesis</topic><topic>Recombinant Proteins - pharmacology</topic><topic>Science</topic><topic>Stem Cells</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Wei</creatorcontrib><creatorcontrib>Wu, Jiyuan</creatorcontrib><creatorcontrib>Yang, Huiqin</creatorcontrib><creatorcontrib>Xiong, Yin</creatorcontrib><creatorcontrib>Jiang, Rui</creatorcontrib><creatorcontrib>Cui, Tianpen</creatorcontrib><creatorcontrib>Ye, Duyun</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</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>Health & Medical Collection</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 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>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>Medical Database</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>Huang, Wei</au><au>Wu, Jiyuan</au><au>Yang, Huiqin</au><au>Xiong, Yin</au><au>Jiang, Rui</au><au>Cui, Tianpen</au><au>Ye, Duyun</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2017-02-01</date><risdate>2017</risdate><volume>24</volume><issue>2</issue><spage>263</spage><epage>275</epage><pages>263-275</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>Abnormal features of the systemic lupus erythematosus (SLE)-derived neutrophils, promoted aberrant immune response, have inspired new studies of the induction of autoimmunity and the development of organ damage in SLE. In this study, we explore the effect of milk fat globule-EGF factor 8 (MFG-E8) on the aberrant nitrification features in pristane-induced lupus. SLE patients and mice with pristane-induced lupus develop autoantibodies associated with MFG-E8 overproduction. However, the deletion of MFG-E8 leads to uncontrolled early pulmonary and peritoneal inflammation and tissue damage in mice with pristane-induced lupus. Consistent with these findings, MFG-E8-deficient mice that are exposed to pristane show enhanced neutrophil accumulation and increased neutrophil death, including apoptosis, necrosis and NETosis, as well as impaired phagocytosis of macrophages. The consequences are the expansion of diffuse pulmonary hemorrhage, increased anti-nuclear antibody, anti-dsDNA antibody and anti-neutrophil cytoplasmic antibody levels, and enhanced immune complexes deposition and neutrophil extracellular traps (NETs) formation in the lung and kidney tissues of MFG-E8-deficient mice exposed to pristane. In patients with SLE and mice with pristane-induced lupus, neutrophil accumulation is elevated, which depends on higher expression of the surface receptor CXCR2. After pretreatment with recombinant MFG-E8, the surface expression of CXCR2 on neutrophil is downregulated, and the MFG-E8 deletion increase CXCR2 expression by ~40%. These studies indicate that MFG-E8 reduces neutrophil migration and NETosis via downregulating surface CXCR2 expression in parallel with its role in the phagocytosis of apoptotic neutrophils, suggesting that MFG-E8 may serve as a therapeutic agent for attenuating the early inflammatory responses of SLE and protect patients from lupus-related damage.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>27768123</pmid><doi>10.1038/cdd.2016.115</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/1 38/79 631/250/1933 692/420/2780 96/31 96/34 Adult Animals Antibodies Antigens Antigens, Surface - genetics Antigens, Surface - metabolism Apoptosis Apoptosis - drug effects Autoantibodies - blood Biochemistry Biomedical and Life Sciences Bronchoalveolar Lavage Fluid - chemistry Bronchoalveolar Lavage Fluid - cytology Cell Biology Cell Cycle Analysis Cell death Cytokines - analysis Disease Models, Animal Down-Regulation - drug effects Female Fullerenes Glomerulonephritis - pathology Granulocytes Hospitals Humans Immunology Kidney - metabolism Kinases Life Sciences Lung - metabolism Lupus Lupus Erythematosus, Systemic - chemically induced Lupus Erythematosus, Systemic - immunology Lupus Erythematosus, Systemic - pathology Medical schools Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Milk Milk Proteins - genetics Milk Proteins - metabolism Neutrophils Neutrophils - cytology Neutrophils - immunology Neutrophils - metabolism Oils & fats Original Paper Pathogenesis Pathophysiology Phagocytosis - drug effects Proteins Receptors, Interleukin-8B - metabolism Recombinant Proteins - biosynthesis Recombinant Proteins - pharmacology Science Stem Cells Young Adult |
| title | Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage |
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