Submitted March 28, 2006
Accepted July 7, 2006
Apoptotic cell thrombospondin-1 and heparin binding
domain lead to dendritic cell phagocytic and tolerizing
states
Alon Krispin, Yaniv Bledi, Mizhir Atallah, Uriel Trahtemberg, Inna Verbovetski, Efrat Nahari, Orly Zelig, Michal Linial, and Dror Mevorach*
Hadassah-Hebrew University Medical Center Jerusalem, Israel
Life Science Institute The Hebrew University, Jerusalem, Israel
Hadassah-Hebrew University Medical Center, Jerusalem, Israel
Transfusion Medicine Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
* Corresponding author; email: mevorachd{at}hadassah.org.il.
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 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 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.
