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Vol. 20, Issue 5, 1280-1288, March 1, 2009

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Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Goethe-University, Institute of Biochemistry I/ZAFES, 60590 Frankfurt, Germany

Submitted October 7, 2008; Revised December 19, 2008; Accepted December 23, 2008
Monitoring Editor: Kunxin Luo

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.

Address correspondence to: Bernhard Brüne (bruene{at}pathobiochemie1.de)

Abbreviations used: AC, apoptotic cells; Adora A_2A, adenosine receptor A_2A; CM, conditioned medium/media; CORM-2, tricarbonyldichloro ruthenium (II) dimer; Deta-NO, diethylenetriamine-NO; DMS, dimethyl-sphingosine; EMSA, electrophoretic mobility shift assay; HO-1, heme oxygenase-1; IDO, indoleamine-2,3-dioxygenase; Jak, Janus kinase; M-CM, macrophage CM; NC, necrotic cells; ptm, point mutation; S1P, sphingosine-1-phosphate; S1P₁, S1P-receptor 1; STATx, STAT response element; TAM, tumor-associated macrophage; VC, viable cells; VEGFA, vascular endothelial growth factor A.

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