S1P Regulation of Macrophage Functions in the Context of Cancer

Weigert, Andreas; Weichand, Benjamin; Brüne, Bernhard

doi:10.2174/187152011797655096

Cited by 22 publications

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“…5). Even though S1PR1 has been linked to macrophage activation , inflammatory cytokine levels in the peritoneal lavage of both experimental groups at day 6 or mRNA levels of macrophage polarization markers did not differ (Supporting Information Fig. 6).…”

Section: Resultsmentioning

confidence: 97%

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Apoptotic cells enhance sphingosine‐1‐phosphate receptor 1 dependent macrophage migration

et al. 2013

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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...

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Section: Resultsmentioning

confidence: 97%

“…Human macrophages express S1PR1–4 , while murine macrophages express mainly S1PR1 and 2 . S1P plays a role in macrophage migration in physiology and pathophysiology . In inflammatory settings, S1PR2 inhibited and S1P3 promoted macrophage recruitment during thioglycollate‐induced peritonitis as well as their motility in vitro .…”

Section: Introductionmentioning

confidence: 99%

Apoptotic cells enhance sphingosine‐1‐phosphate receptor 1 dependent macrophage migration

et al. 2013

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“…S1P receptors are involved in many biological processes and many disease progresses from autoimmunity (3, 8) to atherosclerosis and cancer (9, 10). Despite significant homologies in their sequence and structure, S1P 1-5 have varied tissue distribution, different arrays of downstream G protein coupling, various biochemical and physiological functions, and different receptor fates (4, 11).…”

Section: Introductionmentioning

confidence: 99%

Novel Selective Allosteric and Bitopic Ligands for the S1P₃ Receptor

Bhhatarai

Repetto

et al. 2012

ACS Chem. Biol.

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Sphingosine 1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions, including lymphocyte trafficking and vascular development, by activating G protein-coupled receptors for S1P, namely S1P1 through S1P5. Here we map the S1P3 binding pocket with a novel allosteric agonist (CYM-5541), an orthosteric agonist (S1P), and a novel bitopic antagonist (SPM-242). With a combination of site-directed mutagenesis, ligand competition assay, and molecular modeling, we concluded that S1P and CYM-5541 occupy different chemical spaces in the ligand binding pocket of S1P3. CYM-5541 allowed us to identify an allosteric site where Phe263 is a key gate-keeper residue for its affinity and efficacy. This ligand lacks a polar moiety and the novel allosteric hydrophobic pocket permits S1P3 selectivity of CYM-5541 within the highly similar S1P receptor family. On the other hand, a novel S1P3-selective antagonist, SPM-242, in the S1P3 pocket occupies the ligand binding spaces of both S1P and CYM-5541, showing its bitopic mode of binding. Therefore, our coordinated approach with biochemical data and molecular modeling, based on our recently published S1P1 crystal structure data in a highly conserved set of related receptors with a shared ligand, provides a strong basis for the successful optimization of orthosteric, allosteric, and bitopic modulators of S1P3.

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“…A prominent example of hybrid-type macrophages are tumor-associated macrophages (TAMs) that exhibit healing and tissue remodeling properties that produce inflammatory mediators (IL-6 and IL-23), but also negatively regulate other tumor-associated immune cell populations through IL-10 (230), thus combining the functional properties of all three primary macrophage populations. It is therefore not surprising that transcription factors such as NF-jB and STAT1 (classically activated macrophages), PPARc (wound-healing macrophages), as well as STAT3 and CREB (regulatory macrophages) are connected to the TAM phenotype (319).…”

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Redox Control of Inflammation in Macrophages

Brüne

Dehne²,

Grossmann³

et al. 2013

Antioxidants & Redox Signaling

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Macrophages are present throughout the human body, constitute important immune effector cells, and have variable roles in a great number of pathological, but also physiological, settings. It is apparent that macrophages need to adjust their activation profile toward a steadily changing environment that requires altering their phenotype, a process known as macrophage polarization. Formation of reactive oxygen species (ROS), derived from NADPH-oxidases, mitochondria, or NO-producing enzymes, are not necessarily toxic, but rather compose a network signaling system, known as redox regulation. Formation of redox signals in classically versus alternatively activated macrophages, their action and interaction at the level of key targets, and the resulting physiology still are insufficiently understood. We review the identity, source, and biological activities of ROS produced during macrophage activation, and discuss how they shape the key transcriptional responses evoked by hypoxia-inducible transcription factors, nuclear-erythroid 2-p45-related factor 2 (Nrf2), and peroxisome proliferator-activated receptor-γ. We summarize the mechanisms how redox signals add to the process of macrophage polarization and reprogramming, how this is controlled by the interaction of macrophages with their environment, and addresses the outcome of the polarization process in health and disease. Future studies need to tackle the option whether we can use the knowledge of redox biology in macrophages to shape their mediator profile in pathophysiology, to accelerate healing in injured tissue, to fight the invading pathogens, or to eliminate settings of altered self in tumors.

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S1P Regulation of Macrophage Functions in the Context of Cancer

Cited by 22 publications

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Apoptotic cells enhance sphingosine‐1‐phosphate receptor 1 dependent macrophage migration

Apoptotic cells enhance sphingosine‐1‐phosphate receptor 1 dependent macrophage migration

Novel Selective Allosteric and Bitopic Ligands for the S1P₃ Receptor

Redox Control of Inflammation in Macrophages

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S1P Regulation of Macrophage Functions in the Context of Cancer

Cited by 22 publications

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Apoptotic cells enhance sphingosine‐1‐phosphate receptor 1 dependent macrophage migration

Apoptotic cells enhance sphingosine‐1‐phosphate receptor 1 dependent macrophage migration

Novel Selective Allosteric and Bitopic Ligands for the S1P3 Receptor

Redox Control of Inflammation in Macrophages

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Novel Selective Allosteric and Bitopic Ligands for the S1P₃ Receptor