Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate.
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-X(L) 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.
Weigert
Andreas
A
University of Frankfurt, Institute of Biochemistry I/Center for Drug Research, Development, and Safety (ZAFES), Johann Wolfgang Goethe-University of Frankfurt, Germany.
Johann
Axel M
AM
von Knethen
Andreas
A
Schmidt
Helmut
H
Geisslinger
Gerd
G
Brüne
Bernhard
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D006801:Humans; D019169:Jurkat Cells; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D034741:RNA, Small Interfering / Q000235:genetics; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology
D017077:Culture Media, Conditioned; D008246:Lysophospholipids; D034741:RNA, Small Interfering; C060506:sphingosine 1-phosphate; D019311:Staurosporine; D013110:Sphingosine