scholarly journals Masking of Phosphatidylserine Inhibits Apoptotic Cell Engulfment and Induces Autoantibody Production in Mice

2004 ◽  
Vol 200 (4) ◽  
pp. 459-467 ◽  
Author(s):  
Kenichi Asano ◽  
Miyu Miwa ◽  
Keiko Miwa ◽  
Rikinari Hanayama ◽  
Hiroko Nagase ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Milk Fat ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Peritoneal Macrophages ◽  
Apoptotic Cells ◽  
Autoantibody Production ◽  
Enhanced Production ◽  
Immature Dendritic Cells ◽  
Milk Fat Globule

Apoptotic cells are rapidly phagocytosed by professional phagocytes, such as macrophages and dendritic cells. This process prevents the release of potentially noxious or immunogenic intracellular materials from dying cells, and is thought to play a critical role for the maintenance of normal functions in surrounding tissues. Milk fat globule-EGF-factor 8 (MFG-E8), secreted by activated macrophages and immature dendritic cells, links apoptotic cells and phagocytes, and promotes phagocytosis of apoptotic cells. Here, we report that an MFG-E8 mutant, designated as D89E, carrying a point mutation in an RGD motif, inhibited not only the phagocytosis of apoptotic cells by a wide variety of phagocytes, but also inhibited the enhanced production of IL-10 by thioglycollate-elicited peritoneal macrophages phagocytosing apoptotic cells. When intravenously injected into mice, the D89E protein induced the production of autoantibodies including antiphospholipids antibodies and antinuclear antibodies. The production of autoantibodies was enhanced by the coinjection of syngeneic apoptotic thymocytes. After the induction of autoantibody production by D89E, the treated mice showed a long-term elevation of the titer for autoantibodies, and developed IgG deposition in the glomeruli. These results indicated that the impairment of apoptotic cell phagocytosis led to autoantibody production.

scholarly journals Immature Dendritic Cells Phagocytose Apoptotic Cells via αvβ5 and CD36, and Cross-present Antigens to Cytotoxic T Lymphocytes

1998 ◽  
Vol 188 (7) ◽  
pp. 1359-1368 ◽  
Author(s):  
Matthew L. Albert ◽  
S.Frieda A. Pearce ◽  
Loise M. Francisco ◽  
Birthe Sauter ◽  
Pampa Roy ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Critical Role ◽  
Immature Stage ◽  
Apoptotic Cells ◽  
Cross Tolerance ◽  
Phagocytic Capacity ◽  
Immature Dendritic Cells ◽  
Antigenic Material

Dendritic cells, but not macrophages, efficiently phagocytose apoptotic cells and cross-present viral, tumor, and self-antigens to CD8+ T cells. This in vitro pathway corresponds to the in vivo phenomena of cross-priming and cross-tolerance. Here, we demonstrate that phagocytosis of apoptotic cells is restricted to the immature stage of dendritic cell (DC) development, and that this process is accompanied by the expression of a unique profile of receptors, in particular the αvβ5 integrin and CD36. Upon maturation, these receptors and, in turn, the phagocytic capacity of DCs, are downmodulated. Macrophages engulf apoptotic cells more efficiently than DCs, and although they express many receptors that mediate this uptake, they lack the αvβ5 integrin. Furthermore, in contrast to DCs, macrophages fail to cross-present antigenic material contained within the engulfed apoptotic cells. Thus, DCs use unique pathways for the phagocytosis, processing, and presentation of antigen derived from apoptotic cells on class I major histocompatibility complex. We suggest that the αvβ5 integrin plays a critical role in the trafficking of exogenous antigen by immature DCs in this cross-priming pathway.

Efficient migration of dendritic cells toward lymph node chemokines and induction of TH1 responses require maturation stimulus and apoptotic cell interaction

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1734-1741 ◽  
Author(s):  
Nicolas Bertho ◽  
Henri Adamski ◽  
Louis Toujas ◽  
Martine Debove ◽  
Jean Davoust ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Immune Responses ◽  
Tumor Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Tnf Α

Abstract Dendritic cells (DCs) have the unique ability to initiate primary immune responses, and they can be conditioned for vaccinal purposes to present antigens after the engulfment of apoptotic cells. To recruit the rare antigen-specific naive T cells, DCs require a maturation step and subsequent transport toward lymph node (LN). To date, prostaglandin E2 (PGE2) is the best-characterized compound inducing this LN-directed migration in vitro, but PGE2 may skew the immune responses in a TH2 direction. We demonstrate here that on incubation with apoptotic tumor cells and tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), human monocyte-derived DCs become fully mature and acquire high migratory capacities toward LN-directing chemokines. The migration of TNF-α-treated DCs occurs only after cotreatment with apoptotic cells but not with necrotic cells. DC migration requires CD36 expression and incubation with apoptotic cells in the presence of heat-labile serum components. Moreover, on treatment with apoptotic cells and LPS, the migrating DCs are able to recruit naive T cells to generate TH1 immune responses. Our results show that the cotreatment of DCs with apoptotic tumor cells and inflammatory signals is promising for the design of an antitumoral DC-based vaccine. (Blood. 2005;106:1734-1741)

scholarly journals Persistence of apoptotic cells without autoimmune disease or inflammation in CD14−/− mice

2004 ◽  
Vol 167 (6) ◽  
pp. 1161-1170 ◽  
Author(s):  
Andrew Devitt ◽  
Kate G. Parker ◽  
Carol Anne Ogden ◽  
Ceri Oldreive ◽  
Michael F. Clay ◽  
...  
Keyword(s):  
Autoimmune Disease ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Autoantibody Production ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Surface Receptor ◽  
Anti Inflammatory

Interaction of macrophages with apoptotic cells involves multiple steps including recognition, tethering, phagocytosis, and anti-inflammatory macrophage responses. Defective apoptotic cell clearance is associated with pathogenesis of autoimmune disease. CD14 is a surface receptor that functions in vitro in the removal of apoptotic cells by human and murine macrophages, but its mechanism of action has not been defined. Here, we demonstrate that CD14 functions as a macrophage tethering receptor for apoptotic cells. Significantly, CD14−/− macrophages in vivo are defective in clearing apoptotic cells in multiple tissues, suggesting a broad role for CD14 in the clearance process. However, the resultant persistence of apoptotic cells does not lead to inflammation or increased autoantibody production, most likely because, as we show, CD14−/− macrophages retain the ability to generate anti-inflammatory signals in response to apoptotic cells. We conclude that CD14 plays a broad tethering role in apoptotic cell clearance in vivo and that apoptotic cells can persist in the absence of proinflammatory consequences.

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

2013 ◽  
Vol 20 (9) ◽  
pp. 1230-1240 ◽  
Author(s):  
K Lauber ◽  
H Keppeler ◽  
L E Munoz ◽  
U Koppe ◽  
K Schröder ◽  
...  
Keyword(s):  
Milk Fat ◽  
Apoptotic Cell ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Milk Fat Globule ◽  
Fat Globule

scholarly journals In vivo identification of apoptotic and extracellular vesicle-bound live cells using image-based deep learning

2020 ◽  
Author(s):  
Jan Kranich ◽  
Nikolaos-Kosmas Chlis ◽  
Lisa Rausch ◽  
Ashretha Latha ◽  
Martina Schifferer ◽  
...  
Keyword(s):  
Deep Learning ◽  
Milk Fat ◽  
Great Majority ◽  
Extracellular Vesicle ◽  
Live Cells ◽  
Apoptotic Cells ◽  
Acute Viral Infection ◽  
Convolutional Autoencoder ◽  
Milk Fat Globule

SUMMARYThe in vivo detection of dead cells remains a major challenge due to technical hurdles. Here we present a novel method, where injection of fluorescent Milk fat globule-EGF factor 8 protein (MFG-E8) in vivo combined with imaging flow cytometry and deep learning allows the identification of dead cells based on their surface exposure of phosphatidylserine (PS) and other image parameters. A convolutional autoencoder (CAE) was trained on defined pictures and successfully used to identify apoptotic cells in vivo. However, unexpectedly, these analyses also revealed that the great majority of PS+ cells were not apoptotic, but rather live cells associated with PS+ extracellular vesicles (EVs). During acute viral infection apoptotic cells increased slightly, while up to 30% of lymphocytes were decorated with PS+ EVs of Dendritic cell exosomal origin. The combination of recombinant fluorescent MFG-E8 and the CAE-method will greatly facilitate analyses of cell death and EVs in vivo.

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