title: Heme oxygenase-1 contributes to an alternative macrophage activation profile induced by apoptotic cell supernatants.
abstract: Apoptotic cells (AC) are rapidly engulfed by professional phagocytes such as macrophages to avoid secondary necrosis and thus inflammation. Recognition of AC polarizes macrophages toward an anti-inflammatory phenotype, which shows homology to an alternatively activated M2 macrophage. However, mechanistic details provoking these phenotype alterations are incompletely understood. Here, we demonstrate a biphasic up-regulation of heme oxygenase-1 (HO-1), a protein that bears an antiapoptotic as well as an anti-inflammatory potential, in primary human macrophages, which were exposed to the supernatant of AC. Although the first phase of HO-1 induction at 6 h was accomplished by AC-derived sphingosine-1-phosphate (S1P) acting via S1P receptor 1, the second wave of HO-1 induction at 24 h was attributed to autocrine signaling of vascular endothelial growth factor A (VEGFA), whose expression and release were facilitated by S1P. Whereas VEGFA release from macrophages was signal transducer and activator of transcription (STAT) 1-dependent, vascular endothelial growth factor itself triggered STAT1/STAT3 heterodimer formation, which bound to and activated the HO-1 promoter. Knockdown of HO-1 proved its relevance in facilitating enhanced expression of the antiapoptotic proteins Bcl-2 and Bcl-X(L), as well as the anti-inflammatory adenosine receptor A(2A). These findings suggest that HO-1, which is induced by AC-derived S1P, is critically involved in macrophage polarization toward an M2 phenotype.
authors.affiliation: Goethe-University, Institute of Biochemistry I/ZAFES, 60590 Frankfurt, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Weis
authors.forename: Andreas
authors.initials: A
authors.lastname: Weigert
authors.forename: Andreas
authors.initials: A
authors.lastname: von Knethen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
mesh_terms: D017209:Apoptosis; D019898:Autocrine Communication; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008262:Macrophage Activation / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494811:BCL2L1 protein, human; D017077:Culture Media, Conditioned; D008246:Lysophospholipids; D019253:Proto-Oncogene Proteins c-bcl-2; D049349:Receptors, Lysosphingolipid; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; C060506:sphingosine 1-phosphate; D051547:Heme Oxygenase-1; D013110:Sphingosine