Apoptotic cell thrombospondin-1 and heparin-binding domain lead to dendritic-cell phagocytic and tolerizing states.
Apoptotic cells were shown to induce dendritic cell immune tolerance. We applied a proteomic approach to identify molecules that are secreted from apoptotic monocytes, and thus may mediate engulfment and immune suppression. Supernatants of monocytes undergoing apoptosis were collected and compared using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and differentially expressed proteins were identified using tandem mass spectrometry. Thrombospondin-1 (TSP-1) and its cleaved 26-kDa heparin-binding domain (HBD) were identified. We show that TSP-1 is expressed upon induction of monocyte apoptosis in a caspase-dependent pattern and the HBD is cleaved by chymotrypsin-like serine protease. We further show that CD29, CD36, CD47, CD51, and CD91 simultaneously participate in engulfment induction and generation of an immature dendritic cell (iDC) tolerogenic and phagocytic state. We conclude that apoptotic cell TSP-1, and notably its HBD, creates a signalosome in iDCs to improve engulfment and to tolerate engulfed material prior to the interaction with apoptotic cells.
Krispin
Alon
A
The Laboratory for Cellular and Molecular Immunology, Rheumatology Unit Department of Medicine, Hadassah--Hebrew University Medical Center, POB 12000, Jerusalem 91120, Israel.
Bledi
Yaniv
Y
Atallah
Mizhir
M
Trahtemberg
Uriel
U
Verbovetski
Inna
I
Nahari
Efrat
E
Zelig
Orly
O
Linial
Michal
M
Mevorach
Dror
D
D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis / Q000276:immunology*; D001665:Binding Sites; D003713:Dendritic Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D006493:Heparin; D006801:Humans; D007108:Immune Tolerance; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D010587:Phagocytosis; D040901:Proteomics / Q000379:methods; D019700:Thrombospondin 1 / Q000096:biosynthesis* / Q000302:isolation & purification / Q000378:metabolism
D015703:Antigens, CD; D019700:Thrombospondin 1; D006493:Heparin