Expression of Developmental Endothelial Locus-1 in a Subset of Macrophages for Engulfment of Apoptotic Cells

Hanayama, Rikinari; Tanaka, Masato; Miwa, Keiko; Nagata, Shinji

doi:10.4049/jimmunol.172.6.3876

Cited by 130 publications

(123 citation statements)

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“…When we stimulated differentiated THP-1 macrophages with Dex in vitro, we observed a dose-dependent induction of MFG-E8 expression on mRNA, as well as on protein level (Figure 1c). No such effect was seen with the close MFG-E8 relative developmental endothelial locus-1 (Del-1) 21 or the known GCinducible gene annexin A1 (Anx A1). 22 Interestingly, the majority of MFG-E8 remained associated with the macrophages as confirmed by ELISA measurements of cellular lysates and cell-free culture supernatants (Figure 1e).…”

Section: Resultsmentioning

confidence: 99%

Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids

et al. 2013

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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 À / À 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.

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Section: Resultsmentioning

confidence: 99%

Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids

et al. 2013

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“…It has been shown that milk fat globule EGF 8 (MFG-E8) is an essential factor for the clearance of apoptotic B cells in the spleen and MFG-E8-deficient mice suffer from autoimmunity [19]. Interestingly, apoptotic thymocytes are normally cleared in MFG-E8-deficient mice and MFG-E8 is not expressed in thymic macrophages [23]. In contrast, the clearance of apoptotic cells in mice lacking the Mer receptor tyrosine kinase was severely impaired following the induction of thymocytes apoptosis by Dex, while apoptotic thymocytes were not accumulated in the thymus without Dex challenge [13,24,25].…”

Section: Defective Clearance Of Apoptotic Thymocytes May Trigger Automentioning

confidence: 99%

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

et al. 2009

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Oncostatin M (OSM) has been implicated in immune regulation, though its precise role remains elusive. Here we show that OSM plays a crucial role in the prevention of autoimmune diseases. OSM-deficient mice showed normal development of T cells, B cells and DC; however, their thymus showed hypoplasia and altered medullary structure. Autoantibodies against dsDNA accumulated and glomerulonephritis developed in aged OSMdeficient mice. Apoptotic cells accumulated in the thymus of OSM-deficient mice, and the administration of dexamethasone in young OSM-deficient mice resulted in the massive accumulation of apoptotic thymocytes and production of autoantibodies. These results suggest that OSM plays a key role in the prevention of autoimmune disease by regulating the clearance of apoptotic thymocytes.Key words: Apoptosis . Autoimmunity . Phagocytosis Supporting Information available online IntroductionOncostatin M (OSM) is a member of the IL-6 family of cytokines, and the OSM receptor (OSMR) consists of gp130 and the OSMRb subunit [1]. OSM is produced by a variety of cells including hematopoietic cells and fibroblasts, and is involved in various biological systems [2]. We showed previously that the lack of OSM signaling causes altered bone marrow microenvironment [3,4]. As OSM is also produced by Th1 cells and DC [5][6][7][8], OSM is suggested to play a role in immune reactions. In fact, OSM from activated DC regulates CCL21 expression in microvascular endothelial cells and promotes the trafficking of DC to LN [8].Moreover, Tg mice that express OSM using the lck proximal promoter exhibit thymic hypertrophy [9,10], suggesting that OSM may play a role in T-cell development within the thymic environment.Apoptosis is an essential process for development and homeostasis and defective clearance of apoptotic cells can lead to production of autoantibody by releasing cell debris, breaking peripheral tolerance. Macrophages in various tissues play an essential role in the elimination of apoptotic cells by phagocytosis. A vast majority of thymocytes are depleted by apoptosis during T-cell selections; however, apoptotic cells are barely detected in the thymus, indicating the presence of a mechanism to eliminate apoptotic thymocytes. Dying cells are normally removed rapidly from tissues by phagocytes, without eliciting inflammatory or immune responses. Clearance of apoptotic cells is crucial for prevention of autoimmune diseases [11,12] 1664with impaired macrophage phagocytosis exhibit splenomegaly due to accumulation of massive quantities of apoptotic cells and such defect in humans leads to retinitis pigmentosa [13].Previously, we demonstrated that OSM induces the development of thymic macrophages with strong phagocytic activity from intrathymic progenitors via OSM-responsive thymic epithelial cells (TEC) [14,15]. In this report, we show that OSM deficiency resulted in thymic hypoplasia, defective clearance of apoptotic thymocytes, accumulation of autoantibody and glomerulonephritis. Administration of dexamethasone (Dex) in OSM-defi...

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“…Mouse MFG EGF factor 8 (MFG-E8), called lactadherin in humans, is a 72-kDa glycoprotein secreted from mammary epithelial cells, macrophages, and immature dendritic cells (12)(13)(14)(15). We recently showed that MFG-E8 specifically binds to apoptotic cells by recognizing phosphatidylserine (PS) exposed on the surface of the apoptotic cells and promotes the engulfment of apoptotic cells by phagocytes (12).…”

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Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

Hanayama

Nagata

2005

Proc. Natl. Acad. Sci. U.S.A.

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During the involution of mammary glands, epithelial cells undergo apoptosis and are cleared for the next cycle of lactation. The clearance of apoptotic epithelial cells is mediated by neighboring epithelial cells and by macrophages that migrate into the mammary glands. Here, we report that milk fat globule EGF factor 8 (MFG-E8), a secreted glycoprotein that binds to apoptotic cells by recognizing phosphatidylserine, was expressed by epithelial cells and macrophages in mammary glands and was involved in engulfment of apoptotic cells. A deficiency of MFG-E8 caused the accumulation of a large number of milk fat globules (MFGs) in the mammary ducts during involution, indicating that the excess MFGs were cleared by an MFG-E8-dependent mechanism. The MFG-E8 ؊/؊ mice developed mammary duct ectasia with periductal mastitis, and the redevelopment of the mammary gland for their second litter was impaired. These results demonstrate that MFG-E8-mediated phagocytosis of apoptotic epithelial cells and MFGs is important for efficient involution of mammary glands.exosomes ͉ mastitis ͉ phosphatidylserine M ammary glands are unique mammalian organs that are developed to nurse offspring. For each pregnancy, the glands undergo a cycle of development, lactation, and involution. In each cycle, mammalian epithelial cells proliferate, differentiate, and die. The involution of mammary glands is triggered when the suckling stimulus is lost, usually upon weaning, and milk accumulates in the glands. The involution takes Ϸ10 days in mice and can be divided into two phases (1-3). In the first phase, which is reversible and lasts 48 h after weaning, mammary epithelial cells lose their differentiated function. In the second phase, the basement membranes and extracellular matrix in the mammary glands are degraded by proteases, leading to destruction of the lobular-alveolar architecture of the mammary glands. As involution progresses, mammary epithelial cells are removed and adipocytes concomitantly reappear, and the lobular-alveolar structure is reorganized to approach that of virgin glands (4).During the involution process, epithelial cells undergo apoptosis and are shed into the lumen (5). At the initial stage of involution, these apoptotic cells are thought to be engulfed mainly by neighboring epithelial cells; in the later stage, they seem to be cleared by macrophages that migrate into the gland (3, 6). Milk fat globules (MFGs) are minute globules carrying fat that are secreted from the epithelial cells into the lumen during lactation (7). Upon weaning, many MFGs remain in the lumen, and they seem to be engulfed by epithelial cells lining the lobules in the mammary gland (8). How these epithelial cells and macrophages recognize and engulf apoptotic cells and MFGs has not been well elucidated.Many molecules expressed on the surface of apoptotic cells or phagocytes have been proposed as ligands and receptors for the engulfment of apoptotic cells (9 -11). Mouse MFG EGF factor 8 (MFG-E8), called lactadherin in humans, is a 72-kDa glycoprotein s...

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Expression of Developmental Endothelial Locus-1 in a Subset of Macrophages for Engulfment of Apoptotic Cells

Cited by 130 publications

References 50 publications

Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids

Milk fat globule-EGF factor 8 mediates the enhancement of apoptotic cell clearance by glucocorticoids

Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8

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