Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [70]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family, current gene names have been designated as S1P1R through S1P5R [52]. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [15, 39]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [74, 76]. A crystal structure of an S1P1-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined previously through biochemical and genetic studies [48, 14]. fingolimod (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis [26]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [107, 28, 43, 44].

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Relevance and potential of sphingosine-1-phosphate in vascular inflammatory disease

Biological Chemistry ◽

10.1515/bc.2008.165 ◽

2008 ◽

Vol 389 (11) ◽

Cited By ~ 15

Author(s):

Markus van der Giet ◽

Markus Tölle ◽

Burkhard Kleuser

Keyword(s):

Inflammatory Disease ◽

Therapeutic Option ◽

Vascular Inflammation ◽

Vascular Diseases ◽

Receptor Activation ◽

Pathological Feature ◽

Sphingosine 1 Phosphate ◽

S1p Receptor ◽

Anti Inflammatory

Abstract The typical pathological feature of atherosclerosis is inflammation. In the last years, it has become evident that inhibition of inflammation is one important therapeutic option in atherosclerosis. Recently, sphingolipid sphingosine-1-phosphate (S1P) was identified as a crucial molecule with potent anti-inflammatory properties. Indeed, S1P activates various G protein-coupled receptors, namely S1P1–S1P5. In the vasculature, mainly S1P1–3 receptors are present. FTY720, after phosphorylation to FTY720-P, is an orally active S1P mimetic. FTY720 has been developed for therapy in the field of autoimmune diseases and organ transplantation. In analogy to S1P, FTY720 shows potent anti-inflammatory effects and several groups have tested the in vivo effects of FTY720 on the progression of inflammatory vascular diseases. They could show that S1P receptor activation might lead to a partial inhibition of the progression of atherosclerotic lesions. S1P receptor activation therefore might be a concept for anti-inflammatory drug treatment. However, it is not clear how S1P and FTY720 exactly act on vascular inflammation. This review article gives a brief overview over the known actions of S1P in vascular inflammatory disease.

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Visualizing Sphingosine-1-Phosphate Receptor 1(S1P1) Signaling During Central Nervous System De- and Re-Myelination

10.21203/rs.3.rs-657784/v1 ◽

2021 ◽

Author(s):

Ezzat Hashemi ◽

Hsing-Chuan Tsai ◽

Ezra Yoseph ◽

Monica Moreno ◽

Li-Hao Yeh ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Fluorescent Protein ◽

Demyelinating Disease ◽

Oligodendrocyte Progenitor Cells ◽

Reporter Mice ◽

Sphingosine 1 Phosphate ◽

The Central Nervous System ◽

Green Fluorescent

Abstract Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) mediated by aberrant immune responses. The current immune modulatory therapies are unable to protect and repair the brain damage caused by the immune attack. One of the therapeutic targets for MS is the sphingosine-1-phosphate (S1P) pathways, which signals via sphingosine-1-phosphate receptors 1-5 (S1P1-5), in the CNS and immune cells. In light of the potential neuro-protective properties of S1P signaling, we utilized the S1P1-GFP (Green fluorescent protein) reporter mice in the cuprizone-induced-demyelination model, to investigate the in vivo S1P- S1P1 signaling in the CNS. We observed S1P1 signaling in a subset of neural stem cells in the subventricular zone (SVZ) during demyelination. Additionally, oligodendrocyte progenitor cells in the SVZ and mature oligodendrocytes in the medial corpus callosum (MCC) expressed S1P1 signaling during remyelination. We did not observe S1P1 signaling in neurons and astrocytes in the cuprizone model. This approach was unable to determine S1P1-GFP signaling in the myeloid cells because of their aberrant GFP expression in GFP reporter mice. Significant S1P1 signaling was observed in lymphocytes during demyelination and inflammation. Our findings reveal β-arrestin dependent S1P1 signaling in oligodendrocyte lineage cells, indicating a role of S1P1 signaling during remyelination.

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Lysophospholipid (S1P) receptors (version 2020.5) in the IUPHAR/BPS Guide to Pharmacology Database

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f135/2020.5 ◽

2020 ◽

Vol 2020 (5) ◽

Author(s):

Victoria Blaho ◽

Jerold Chun ◽

Danielle Jones ◽

Deepa Jonnalagadda ◽

Yasuyuki Kihara ◽

...

Keyword(s):

Ligand Binding ◽

Radioligand Binding ◽

Cell Types ◽

Receptor Activation ◽

Multiple Organ ◽

S1p Receptors ◽

Organ Systems ◽

Sphingosine 1 Phosphate ◽

Heterologous Expression Systems

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [86]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family, current gene names have been designated as S1P1R through S1P5R [66, 16, 109]. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [18, 48]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [91, 93]. A crystal structure of an S1P1-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation determined previously through biochemical and genetic studies [62, 17]. fingolimod (FTY720), the first drug to target any of the lysophospholipid receptors, binds to four of the five S1PRs, and was the first oral therapy for multiple sclerosis )MS) [32]. siponimod and ozanimod that target S1P1 and S1P5 are also FDA approved for the treatment of various MS forms [16, 109]. The mechanisms of action of fingolimod and other S1PR modulating drugs in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [126, 34, 56, 57].

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Lysophospholipid (S1P) receptors in GtoPdb v.2021.2

IUPHAR/BPS Guide to Pharmacology CITE ◽

10.2218/gtopdb/f135/2021.2 ◽

2021 ◽

Vol 2021 (2) ◽

Author(s):

Victoria Blaho ◽

Jerold Chun ◽

Danielle Jones ◽

Deepa Jonnalagadda ◽

Yasuyuki Kihara ◽

...

Keyword(s):

Ligand Binding ◽

Radioligand Binding ◽

Mouse Genome Informatics ◽

Cell Types ◽

Receptor Activation ◽

Gene Nomenclature ◽

S1p Receptors ◽

Organ Systems ◽

Sphingosine 1 Phosphate

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [89]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [16, 112], the receptors are currently designated as S1P1R through S1P5R [69, 16, 112]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors have been knocked-out in mice constitutively and in some cases, conditionally. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [18, 49]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [94, 96]. A crystal structure of an S1P1-T4 fusion protein confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [65, 17]. fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [33]. siponimod and ozanimod that target S1P1 and S1P5 are also FDA approved for the treatment of various MS forms [16, 112]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [129, 35, 59, 60].

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CRISPR/Cas9 mediated dual fluorescent reporter mice to study spatial bone genomics of osteoblasts and osteoclasts in the local in vivo environment

Bone Reports ◽

10.1016/j.bonr.2021.100871 ◽

2021 ◽

Vol 14 ◽

pp. 100871

Author(s):

Dilara Yilmaz ◽

Yannick Fischer ◽

Sandra Zimmermann ◽

Gaonhae Hwang ◽

Ralph Müller ◽

...

Keyword(s):

Fluorescent Reporter ◽

Reporter Mice

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Interleukin-11-expressing fibroblasts have a unique gene signature correlated with poor prognosis of colorectal cancer

Nature Communications ◽

10.1038/s41467-021-22450-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Takashi Nishina ◽

Yutaka Deguchi ◽

Daisuke Ohshima ◽

Wakami Takeda ◽

Masato Ohtsuka ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Cells ◽

Human Cancer ◽

Tumor Development ◽

Gene Signature ◽

Free Survival ◽

Expression Of Genes ◽

Reporter Mice ◽

Interleukin 11

AbstractInterleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11+) cells are not fully understood. To characterize IL-11+ cells in vivo, we generate Il11 reporter mice. IL-11+ cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11+ cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11+ fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11+ fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.

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Adipocyte death triggers a pro-inflammatory response and induces metabolic activation of resident macrophages

Cell Death and Disease ◽

10.1038/s41419-021-03872-9 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Andreas Lindhorst ◽

Nora Raulien ◽

Peter Wieghofer ◽

Jens Eilers ◽

Fabio M. V. Rossi ◽

...

Keyword(s):

Inflammatory Response ◽

Metabolic Activation ◽

Degradation Process ◽

Critical Threshold ◽

Low Grade ◽

Blood Monocytes ◽

Threshold Size ◽

Laser Injury ◽

Reporter Mice

AbstractA chronic low-grade inflammation within adipose tissue (AT) seems to be the link between obesity and some of its associated diseases. One hallmark of this AT inflammation is the accumulation of AT macrophages (ATMs) around dead or dying adipocytes, forming so-called crown-like structures (CLS). To investigate the dynamics of CLS and their direct impact on the activation state of ATMs, we established a laser injury model to deplete individual adipocytes in living AT from double reporter mice (GFP-labeled ATMs and tdTomato-labeled adipocytes). Hence, we were able to detect early ATM-adipocyte interactions by live imaging and to determine a precise timeline for CLS formation after adipocyte death. Further, our data indicate metabolic activation and increased lipid metabolism in ATMs upon forming CLS. Most importantly, adipocyte death, even in lean animals under homeostatic conditions, leads to a locally confined inflammation, which is in sharp contrast to other tissues. We identified cell size as cause for the described pro-inflammatory response, as the size of adipocytes is above a critical threshold size for efferocytosis, a process for anti-inflammatory removal of dead cells during tissue homeostasis. Finally, experiments on parabiotic mice verified that adipocyte death leads to a pro-inflammatory response of resident ATMs in vivo, without significant recruitment of blood monocytes. Our data indicate that adipocyte death triggers a unique degradation process and locally induces a metabolically activated ATM phenotype that is globally observed with obesity.

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