Submitted April 4, 2006
Accepted April 25, 2006
Apoptotic cells promote macrophage survival by releasing
the anti-apoptotic mediator sphingosine-1-phosphate
Andreas Weigert, Axel M Johann, Andreas von Knethen, Helmut Schmidt, Gerd Geisslinger, and Bernhard Brune*
University of Frankfurt Medical School, Frankfurt, Germany
University of Frankfurt Medical School, Frankfurt Germany
* Corresponding author; email: bruene{at}zbc.kgu.de.
Programmed cell death is vital for a number of patho-
physiological settings. Apoptotic cells are rapidly
engulfed by phagocytes i.e. macrophages which in turn
acquire an anti-inflammatory phenotype known
as ‘ alternative activation’ or the M2-type.
Here we show
that interaction of apoptotic cells with macrophages
attenuates cell death pathways in the latter ones.
Protection of human macrophages required
phosphoinositide 3-kinase (PI3K), extracellular signal-
regulated kinase 1/2 (ERK1/2) and Ca2+
signaling, and
correlated with Bcl-XL and Bcl-2 up-regulation
as well
as Ser136-Bad phosphorylation. Unexpectedly neither
phagocytosis nor binding of apoptotic debris to the
phagocyte was necessary to induce protection.
Surprisingly, apoptotic cells released sphingosine-1-
phosphate (S1P), mainly derived from sphingosine kinase
2, as a survival messenger. This points to an active
role of apoptotic cells in preventing cell destruction
in their neighborhood with implications for innate
immunity and inflammation.
