Journal
CELLULAR SIGNALLING
Volume 25, Issue 12, Pages 2762-2768Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2013.08.045
Keywords
Efferocytosis; Macrophages; Alternative activation; Sepsis; 5-Lipoxygenase
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Funding
- Deutsche Forschungsgemeinschaft [KN493/9-2, SFB 815 TP3, SFB 1039 TP A02, SFB 1039 TP B04, BR-999]
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Macrophage polarization to an anti-inflammatory phenotype upon contact with apoptotic cells is a contributing hallmark to immune suppression during the late phase of sepsis. Although the peroxisome proliferator-activated receptor gamma (PPAR gamma) supports this macrophage phenotype switch, it remains elusive how apoptotic cells activate PPAR gamma. Assuming that a molecule causing PPAR gamma activation in macrophages originates in the cell membrane of apoptotic cells we analyzed lipid rafts from apoptotic, necrotic, and living human Jurkat T cells which showed the presence of 5-lipoxygenase (5-LO) in lipid rafts of apoptotic cells only. Incubating macrophages with lipid rafts of apoptotic, but not necrotic or living cells, induced PPAR responsive element (PPRE)-driven mRuby reporter gene expression in RAW 264.7 macrophages stably transduced with a 4xPPRE containing vector. Experiments with lipid rafts of apoptotic murine EL4 T cells revealed similar results. To verify the involvement of 5-LO in activating PPAR gamma in macrophages, Jurkat T cells were incubated with the 5-LO inhibitor MK-866 prior to induction of apoptosis, which failed to induce mRuby expression. Similar results were obtained with lipid rafts of apoptotic EL4 T cells preexposed to the 5-LO inhibitors zileuton and CJ-13610. Interestingly, Jurkat T cells overexpressing 5-LO failed to activate PPAR gamma in macrophages, while their 5-LO overexpressing apoptotic counterparts did. Our results suggest that during apoptosis 5-LO gets associated with lipid rafts and synthesizes ligands that in turn stimulate PPAR gamma in macrophages. (C) 2013 Elsevier Inc. All rights reserved.
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