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Wei Huang, Jiyuan Wu, Huiqin Yang, Yin Xiong, Rui Jiang, Tianpen Cui, Duyun Ye
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...
October 21, 2016: Cell Death and Differentiation
Kathrin Sinningen, Sylvia Thiele, Lorenz C Hofbauer, Martina Rauner
Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that is abundantly expressed in various tissues and has a pivotal role in the phagocytic clearance of apoptotic cells. However, MFG-E8 has also gained significant attention because of its wide range of functions in autoimmunity, inflammation and tissue homeostasis. More recently, MFG-E8 has been identified as a critical regulator of bone homeostasis, being expressed in both, osteoblasts and osteoclasts. In addition, it was shown that MFG-E8 fulfils an active role in modulating inflammatory processes, suggesting an anti-inflammatory role of MFG-E8 and proposing it as a novel therapeutic target for inflammatory diseases...
2016: BoneKEy Reports
Xiao Wang, Liangliang Hao, Heng-Fu Bu, Alexander W Scott, Ke Tian, Fangyi Liu, Isabelle G De Plaen, Yulan Liu, Chad A Mirkin, Xiao-Di Tan
Milk fat globule-EGF factor 8 (MFG-E8) maintains the intestinal homeostasis by enhancing enterocyte migration and attenuating inflammation. We previously reported that sepsis is associated with down-regulation of intestinal MFG-E8 and impairment of enterocyte migration. Here, we showed that impairment of intestinal epithelial cell migration occurred in lipopolysaccharide (LPS)-induced septic mice. Treatment of RAW264.7 cells (a murine macrophage-like cell line) with LPS increased expression of miR-99b, a microRNA that is predicted to target mouse MFG-E8 3'UTR...
2016: Scientific Reports
Keiko Sakamoto, Yuji Fukushima, Koyu Ito, Michiyuki Matsuda, Shigekazu Nagata, Nagahiro Minato, Masakazu Hattori
Disposal of apoptotic cells is important for tissue homeostasis. Defects in this process in immune tissues may lead to breakdown of self-tolerance against intracellular molecules, including nuclear components. Development of diverse anti-nuclear Abs (ANAs) is a hallmark of lupus, which may arise, in part, due to impaired apoptotic cell clearance. In this work, we demonstrate that spontaneous germinal centers (GCs) in lupus-prone mice contain significantly elevated levels of unengulfed apoptotic cells, which are otherwise swiftly engulfed by tingible body macrophages...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Young-Su Yi
Inflammation involves a series of complex biological processes mediated by innate immunity for host defense against pathogen infection. Chronic inflammation is considered to be one of the major causes of serious diseases, including a number of autoimmune/inflammatory diseases, cancers, cardiovascular diseases, and neurological diseases. Milk fat globule-epidermal growth factor 8 (MFG-E8) is a secreted protein found in vertebrates and was initially discovered as a critical component of the milk fat globule. Previously, a number of studies have reported that MFG-E8 contributes to various biological functions including the phagocytic removal of damaged and apoptotic cells from tissues, the induction of VEGF-mediated neovascularization, the maintenance of intestinal epithelial homeostasis, and the promotion of mucosal healing...
2016: Mediators of Inflammation
Liang Yu, Rong Hu, Claretta Sullivan, R James Swanson, Sergio Oehninger, Ying-Pu Sun, Silvina Bocca
This study investigated the role of milk fat globule-epidermal growth factor-factor 8 (MFGE8) in TGF-β-induced epithelial-mesenchymal transition (EMT) of endometrial epithelial cells. These were in vitro studies using human endometrial epithelial cells and mouse blastocysts. We investigated the ability of TGF-β to induce EMT in endometrial epithelial cells (HEC-1A) by assessment of cytological phenotype (by light and atomic force microscopy), changes in expression of the markers of cell adhesion/differentiation E- and N-cadherin, and of the transcription factor Snail (by immunofluorescence and immunoblotting), and competence to support embryo attachment in a mouse blastocyst outgrowth assay...
September 2016: Reproduction: the Official Journal of the Society for the Study of Fertility
Urte Neniskyte, Michael Fricker, Guy C Brown
Alzheimer's disease is characterized by brain plaques of amyloid beta and by neuronal loss, but it is unclear how amyloid beta causes neuronal loss and how to prevent this loss. We have previously shown that amyloid beta causes neuronal loss by inducing microglia to phagocytose neurons, and here we investigated whether protein kinase Cs and NADPH oxidase were involved in this. The loss of neurons induced by amyloid beta in co-cultures of primary glia and neurons was completely prevented by inhibiting protein kinase Cs with Gö6976 or Gö6983...
June 4, 2016: International Journal of Biochemistry & Cell Biology
Marie-Joëlle Brissette, Patrick Laplante, Shijie Qi, Mathieu Latour, Jean-François Cailhier
Mediators released by apoptotic renal resident cells play a crucial role in modification of the inflammatory microenvironment. We have demonstrated that milk fat globule epidermal growth factor 8 (MFG-E8) is released by apoptotic cells, which results in reduced proinflammatory cytokine production by macrophages. The present study was designed to study the role of MFG-E8 on the modulation of tissue damage and macrophage phenotype in a renal inflammatory model, unilateral ureteral obstruction (UUO). C57BL/6 WT or MFG-E8 KO mice underwent ureteral ligation for 3, 7, and 14 d to evaluate renal injury...
June 3, 2016: Journal of Leukocyte Biology
Kazuya Yamada, Akihiko Uchiyama, Akihito Uehara, Buddhini Perera, Sachiko Ogino, Yoko Yokoyama, Yuko Takeuchi, Mark C Udey, Osamu Ishikawa, Sei-Ichiro Motegi
Secretion of the powerful angiogenic factor MFG-E8 by pericytes can bypass the therapeutic effects of anti-VEGF therapy, but the mechanisms by which MFG-E8 acts are not fully understood. In this study, we investigated how this factor acts to promote the growth of melanomas that express it. We found that mouse bone marrow-derived mesenchymal stromal cells (MSC) expressed a substantial amount of MFG-E8. To assess its expression from this cell type, we implanted melanoma cells and MSC derived from wild type (WT) or MFG-E8 deficient [knockout (KO)] into mice and monitored tumor growth...
July 15, 2016: Cancer Research
Amitava Das, Subhadip Ghatak, Mithun Sinha, Scott Chaffee, Noha S Ahmed, Narasimham L Parinandi, Eric S Wohleb, John F Sheridan, Chandan K Sen, Sashwati Roy
Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a peripheral glycoprotein that acts as a bridging molecule between the macrophage and apoptotic cells, thus executing a pivotal role in the scavenging of apoptotic cells from affected tissue. We have previously reported that apoptotic cell clearance activity or efferocytosis is compromised in diabetic wound macrophages. In this work, we test the hypothesis that MFG-E8 helps resolve inflammation, supports angiogenesis, and accelerates wound closure...
June 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Haruka Kimura-Kojima, Kana Unuma, Takeshi Funakoshi, Chizuru Kato, Ayumi Komatsu, Toshihiko Aki, Koichi Uemura
The aim of this study was to examine the possible involvement of smooth muscle cell remodeling and the induction of MFG-E8 (milk fat globule protein epidermal growth factor-VIII) in vascular pathophysiology during cocaine administration in cultured cells and rats. Cocaine exerts bifurcate effects on vascular cells; it stimulates vasoconstriction through enhancement of catecholamine release at low doses, while it suppresses cardiovascular functions through inhibition of ion channels at high doses. Short-term exposure to a high concentration of cocaine (3 mM, 24 hr) resulted in cell death of A7r5 rat aorta-derived smooth muscle cells...
April 2016: Journal of Toxicologic Pathology
Erick R Castellanos, Claudio Ciferri, Wilson Phung, Wendy Sandoval, Marissa L Matsumoto
Milk fat globule-epidermal growth factor-factor 8 (MFG-E8), as its name suggests, is a major glycoprotein component of milk fat globules secreted by the mammary epithelium. Although its role in milk fat production is unclear, MFG-E8 has been shown to act as a bridge linking apoptotic cells to phagocytes for removal of these dying cells. MFG-E8 is capable of bridging these two very different cell types via interactions through both its epidermal growth factor (EGF)-like domain(s) and its lectin-type C domains...
August 2016: Protein Expression and Purification
Valentino Rački, Daniela Petrić, Natalia Kučić, Nika Gržeta, Kristina Jurdana, Ika Rončević-Gržeta
Cortical gray matter loss in schizophrenia remains a great therapeutic difficulty. Each psychotic episode causes irreversible cortical gray matter loss, that causes the patients to never regain their previous state of functioning. Microglial cells are part of the innate immune system and their functions, among others, include phagocytosis and release of neurotrophic factors. They have a key impact on developmental and plasticity-induced removal of neuronal precursors, live-but-stressed neurons and synapses, while also stimulating synaptic growth and development...
March 2016: Medical Hypotheses
Jing Cao, Christopher Murat, Weijun An, Xiang Yao, John Lee, Sandra Santulli-Marotto, Ian R Harris, George Inana
Retinal pigment epithelium (RPE) cells perform many functions crucial for retinal preservation and vision. RPE cell dysfunction results in various retinal degenerative diseases, such as retinitis pigmentosa and age-related macular degeneration (AMD). Currently, there are no effective treatments for retinal degeneration except for a small percentage of individuals with exudative AMD. Cell therapies targeting RPE cells are being developed in the clinic for the treatment of retinal degeneration. Subretinal injection of human umbilical tissue-derived cells (hUTC) in the Royal College of Surgeons (RCS) rat model of retinal degeneration was shown to preserve photoreceptors and visual function...
February 2016: Stem Cells
Weng-Lang Yang, Archna Sharma, Fangming Zhang, Shingo Matsuo, Zhimin Wang, Haichao Wang, Ping Wang
INTRODUCTION: Sepsis involves overwhelming inflammatory responses with subsequent immune-suppression that can lead to multiple organ dysfunction and ultimately death. Milk fat globule epidermal growth factor-factor 8 (MFG-E8) is a secretory protein found to have multiple biological activities against autoimmune and inflammatory diseases. MFG-E8 contains an Arg-Gly-Asp (RGD) motif involved in cell-cell and cell-matrix interactions. In sepsis, excessive neutrophils migration through endothelial cells and matrix to sites of inflammation results in organ damage...
October 28, 2015: Critical Care: the Official Journal of the Critical Care Forum
Miho Chikazawa, Natsuki Otaki, Takahiro Shibata, Takehiko Yasueda, Tsukasa Matsuda, Koji Uchida
BACKGROUND: Milk fat globule epidermal growth factor 8 (MFG-E8) is a protein that binds to apoptotic cells by recognizing phosphatidylserine and enhances the engulfment of apoptotic cells by macrophages. Many apoptotic cells are left unengulfed in the germinal centers of the spleen in the MFG-E8-deficient (MFG-E8(-/-)) mice, and these mice develop an autoimmune disease. RESULTS: We found that the MFG-E8 deficiency was accompanied by the increased production of immunoglobulins...
October 2014: Free Radical Biology & Medicine
Yuan Tan, Bodour AlKhamees, Deyong Jia, Li Li, Jean-François Couture, Daniel Figeys, Masahisa Jinushi, Lisheng Wang
The molecules and mechanisms pertinent to the low immunogenicity of undifferentiated embryonic stem cells (ESCs) remain poorly understood. Here, we provide evidence that milk fat globule epidermal growth factor 8 (MFG-E8) is a vital mediator in this phenomenon and directly suppresses T cell immune responses. MFG-E8 is enriched in undifferentiated ESCs but diminished in differentiated ESCs. Upregulation of MFG-E8 in ESCs increases the successful engraftment of both undifferentiated and differentiated ESCs across major histocompatibility complex barriers...
November 10, 2015: Stem Cell Reports
Elise Albus, Kathrin Sinningen, Maria Winzer, Sylvia Thiele, Ulrike Baschant, Anke Hannemann, Julia Fantana, Anne-Kathrin Tausche, Henri Wallaschofski, Matthias Nauck, Henry Völzke, Sylvia Grossklaus, Triantafyllos Chavakis, Mark C Udey, Lorenz C Hofbauer, Martina Rauner
Milk fat globule-epidermal growth factor 8 (MFG-E8) is an anti-inflammatory glycoprotein that mediates the clearance of apoptotic cells and is implicated in the pathogenesis of autoimmune and inflammatory diseases. Because MFG-E8 also controls bone metabolism, we investigated its role in rheumatoid arthritis (RA), focusing on inflammation and joint destruction. The regulation of MFG-E8 by inflammation was assessed in vitro using osteoblasts, in arthritic mice and in patients with RA. K/BxN serum transfer arthritis (STA) was applied to MFG-E8 knock-out mice to assess its role in the pathogenesis of arthritis...
March 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Cindy Cen, Monowar Aziz, Weng-Lang Yang, Jeffrey Nicastro, Gene F Coppa, Ping Wang
BACKGROUND: Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein with a known role in inflammation. In sepsis, interleukin (IL)-17 acts as a proinflammatory cytokine to exaggerate systemic inflammation. We hypothesize that MFG-E8 downregulates IL-17 expression in sepsis. METHODS: Sepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Recombinant mouse MFG-E8 (rmMFG-E8) at a dosage of 20 μg/kg body weight or phosphate-buffered saline was concurrently injected...
February 2016: Surgery
S Zhang, J G Xie, B T Su, J L Li, N Hu, J Chen, G W Luo, T P Cui
Milk fat globule epidermal growth factor 8 (MFG-E8) is an opsonin involved in the phagocytosis of apoptotic cells. In patients with chronic obstructive pulmonary disease (COPD), apoptotic cell clearance is defective. However, whether aberrant MFG-E8 expression is involved in this defect is unknown. In this study, we examined the expression of MFG-E8 in COPD patients. MFG-E8, interleukin (IL)-1β and transforming growth factor (TGF)-β levels were measured in the plasma of 96 COPD patients (93 males, 3 females; age range: 62...
November 2015: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
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