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Blood, 1 September 2006, Vol. 108, No. 5, pp. 1635-1642.
Prepublished online as a Blood First Edition Paper on May 11, 2006; DOI 10.1182/blood-2006-04-014852.
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IMMUNOBIOLOGY
Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate
Andreas Weigert,
Axel M. Johann,
Andreas von Knethen,
Helmut Schmidt,
Gerd Geisslinger, and
Bernhard Brüne
From the Institute of Biochemistry I/Center for Drug Research, Development, and Safety (ZAFES) and the Institute of Clinical Pharmacology/ZAFES, Johann Wolfgang Goethe-University of Frankfurt, Germany.
Programmed cell death is vital for a number of pathophysiologic settings. Apoptotic cells are rapidly engulfed by phagocytes (ie, 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. 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.
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