title: Milk fat globule-EGF factor 8 suppresses the aberrant immune response of systemic lupus erythematosus-derived neutrophils and associated tissue damage.
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.
authors: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Laboratory of Clinical Immunology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Wei
authors: W
authors: Huang
authors: Department of Dermatology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Jiyuan
authors: J
authors: Wu
authors: Department of Rheumatology and Immunology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Huiqin
authors: H
authors: Yang
authors: Department of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, China.
authors: Yin
authors: Y
authors: Xiong
authors: Laboratory of Clinical Immunology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Rui
authors: R
authors: Jiang
authors: Laboratory of Clinical Immunology, Wuhan No.1 Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Tianpen
authors: T
authors: Cui
authors: Department of Pathophysiology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors: Duyun
authors: D
authors: Ye
mesh_terms: D000328:Adult; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001323:Autoantibodies / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D037741:Fullerenes; D005921:Glomerulonephritis / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000954:Antigens, Surface; D001323:Autoantibodies; D016207:Cytokines; D037741:Fullerenes; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D023063:Receptors, Interleukin-8B; D011994:Recombinant Proteins; C530172:pristine (C60)