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.

Inflammatory reactions are initiated to eliminate pathogens, but also to promote repair of damaged tissue after acute inflammation is terminated. In this regard, macrophages play a prominent role during induction as well as resolution of inflammation and injury in various organs including the kidney. The present study describes a mechanism for renal tissue regeneration after ischaemia/reperfusion injury. Following injury, apoptotic cell‐derived sphingosine‐1‐phosphate (S1P) or exogenously administered sphingosine analogue FTY720 activates macrophages to support the proliferation and healing of renal epithelium, once inflammatory conditions are terminated. Both suppression of inflammation and renal regeneration might require S1P receptor 3 (S1P3) signalling and downstream release of neutrophil gelatinase‐associated lipocalin (NGAL/Lcn‐2) from macrophages. Overall, our data point to a macrophage‐dependent S1P‐S1P3‐Lcn‐2 axis that might be beneficial for restoration of kidney function after an ischaemic insult. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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The lipid sphingosine-1-phosphate (S1P) is a chemokine for a variety of immune cells including lymphocytes and monocytes. Migration toward S1P is determined by the S1P receptor expression profile, with S1PR1/3 (where S1PR is S1P receptor) stimulating and S1PR2 attenuating migration. However, the impact and physiological significance of S1P-induced migration of macrophages is largely unclear. We observed that alternative activation of human macrophages, by IL-4 or apoptotic cells (ACs), enhanced S1PR1 expression. Moreover, ACs provoked macrophage migration toward S1P in an S1PR1-dependent manner as confirmed by pharmacological receptor inhibition and S1PR1-deficient murine macrophages. In a mouse model of resolving peritoneal inflammation, F4/80-driven deletion of S1PR1 reduced postinflammatory macrophage emigration from inflammatory sites. S1PR1 expression on macrophages might, therefore, be relevant for restoring tissue homeostasis during the resolution of inflammation. Keywords: Macrophage activation r Peritonitis r Resolution of inflammation r Sphingolipids r ZymosanAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMacrophages are innate immune cells that originate from primitive hematopoietic progenitors or blood-derived monocytes during inflammation [1]. Unlike resident macrophages, which largely regulate their numbers via local proliferation, mobilized monocytederived macrophages, like dendritic cells (DCs), rely on their high motility to extravasate tissues during inflammation. Resolution of inflammation requires clearance of monocyte-derived macrophages excess from the inflammation sites, which includes their migration to the lymphatic system [2]. The molecular mechanisms that guide macrophages toward the lymphatic system are unknown. One possible molecule involved in the process Correspondence: Dr. Bernhard Brüne e-mail: b.bruene@biochem.uni-frankfurt.de is sphingosine-1-phosphate (S1P). Detectable quantities of this sphingolipid are, at steady-state conditions, present only in blood and lymph of mammals [3]. Migration toward S1P is controlled by the relative expression of five specific S1P receptors (S1PR1-5), which are partially redundant in their cellular signaling capacity. S1P coupling to S1PR1 and S1PR3 favors migration, whereas S1PR2 counteracts this process [3].Mononuclear phagocytes express multiple S1PRs [4], which are species, cell type, and activation specific. Human monocytes express S1PR1, 2, and 4. Human macrophages express S1PR1-4 [5], while murine macrophages express mainly S1PR1 and 2 [6]. S1P plays a role in macrophage migration in physiology and pathophysiology [7]. In inflammatory settings, S1PR2 inhibited and * These authors contributed equally to this article.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 3306-3313 Innate Immunity 3307 S1P3 promoted macrophage recruitment during thioglycollateinduced peritonitis as well as their motility in vitro [6,8]. During maturation, DCs change S1PR expression from S...

Triple-negative breast cancers (TNBC) are especially refractory to treatment due to their negative hormone receptor and ErbB2/HER2 status. Therefore, the identification of cancer-associated deregulated signaling pathways is necessary to develop improved targeted therapies. Here, we show that expression of the ceramide transfer protein CERT is reduced in TNBCs. CERT transfers ceramide from the endoplasmic reticulum to the Golgi complex for conversion into sphingomyelin (SM). We provide evidence that by regulating cellular SM levels, CERT determines the signaling output of the EGF receptor (EGFR/ErbB1), which is upregulated in approximately 70% of TNBCs. CERT downregulation in breast cancer cells enhanced ErbB1 lateral mobility, ligand-induced autophosphorylation, internalization, and chemotaxis. Together, our findings provide a link between lipid metabolism at the Golgi with signaling at the plasma membrane, thereby implicating CERT loss in the progression of TNBCs. Cancer Res; 72(11); 2855-66. Ó2012 AACR.