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Sphingosine 1-phosphate receptor 1 signaling in macrophages reduces atherosclerosis in LDL receptor–deficient mice

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Title: Sphingosine 1-phosphate receptor 1 signaling in macrophages reduces atherosclerosis in LDL receptor–deficient mice
Authors: Poti F., Scalera E., Feuerborn R., Fischer J., Arndt L., Varga G., Pardali E., Seidl M. D., Fobker M., Liebisch G., Hesse B., Lukasz A. H., Rossaint J., Kehrel B. E., Rosenbauer F., Renne T., Christoffersen C., Simoni M., Burkhardt R., Nofer J. -R.
Contributors: Poti, F., Scalera, E., Feuerborn, R., Fischer, J., Arndt, L., Varga, G., Pardali, E., Seidl, M. D., Fobker, M., Liebisch, G., Hesse, B., Lukasz, A. H., Rossaint, J., Kehrel, B. E., Rosenbauer, F., Renne, T., Christoffersen, C., Simoni, M., Burkhardt, R., Nofer, J. -R.
Publication Year: 2024
Collection: Archivio della ricerca dell'Università di Modena e Reggio Emilia (Unimore: IRIS)
Subject Terms: Atherosclerosi, Inflammation, Lipoprotein, Macrophage, Vascular biology
Description: Sphingosine 1-phosphate (S1P) is a lysosphingolipid with antiatherogenic properties, but mechanisms underlying its effects remain unclear. We here investigated atherosclerosis development in cholesterol-rich diet–fed LDL receptor–deficient mice with high or low overexpression levels of S1P receptor 1 (S1P1) in macrophages. S1P1-overexpressing macrophages showed increased activity of transcription factors PU.1, interferon regulatory factor 8 (IRF8), and liver X receptor (LXR) and were skewed toward an M2-distinct phenotype characterized by enhanced production of IL-10, IL-1RA, and IL-5; increased ATP-binding cassette transporter A1– and G1–dependent cholesterol efflux; increased expression of MerTK and efferocytosis; and reduced apoptosis due to elevated B cell lymphoma 6 and Maf bZIP B. A similar macrophage phenotype was observed in mice administered S1P1-selective agonist KRP203. Mechanistically, the enhanced PU.1, IRF8, and LXR activity in S1P1-overexpressing macrophages led to downregulation of the cAMP-dependent PKA and activation of the signaling cascade encompassing protein kinases AKT and mTOR complex 1 as well as the late endosomal/lysosomal adaptor MAPK and mTOR activator 1. Atherosclerotic lesions in aortic roots and brachiocephalic arteries were profoundly or moderately reduced in mice with high and low S1P1 overexpression in macrophages, respectively. We conclude that S1P1 signaling polarizes macrophages toward an antiatherogenic functional phenotype and countervails the development of atherosclerosis in mice.
Document Type: article in journal/newspaper
Language: English
Relation: info:eu-repo/semantics/altIdentifier/pmid/39531328; info:eu-repo/semantics/altIdentifier/wos/WOS:001381847200001; volume:9; issue:24; firstpage:N/A; lastpage:N/A; journal:JCI INSIGHT; https://hdl.handle.net/11380/1373952
DOI: 10.1172/jci.insight.158127
Availability: https://hdl.handle.net/11380/1373952
https://doi.org/10.1172/jci.insight.158127
Rights: info:eu-repo/semantics/openAccess ; license:[IR] creative-commons ; license uri:http://creativecommons.org/licenses/by/4.0/
Accession Number: edsbas.2B964CAE
Database: BASE
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  Label: Title
  Group: Ti
  Data: Sphingosine 1-phosphate receptor 1 signaling in macrophages reduces atherosclerosis in LDL receptor–deficient mice
– Name: Author
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  Data: <searchLink fieldCode="AR" term="%22Poti+F%2E%22">Poti F.</searchLink><br /><searchLink fieldCode="AR" term="%22Scalera+E%2E%22">Scalera E.</searchLink><br /><searchLink fieldCode="AR" term="%22Feuerborn+R%2E%22">Feuerborn R.</searchLink><br /><searchLink fieldCode="AR" term="%22Fischer+J%2E%22">Fischer J.</searchLink><br /><searchLink fieldCode="AR" term="%22Arndt+L%2E%22">Arndt L.</searchLink><br /><searchLink fieldCode="AR" term="%22Varga+G%2E%22">Varga G.</searchLink><br /><searchLink fieldCode="AR" term="%22Pardali+E%2E%22">Pardali E.</searchLink><br /><searchLink fieldCode="AR" term="%22Seidl+M%2E+D%2E%22">Seidl M. D.</searchLink><br /><searchLink fieldCode="AR" term="%22Fobker+M%2E%22">Fobker M.</searchLink><br /><searchLink fieldCode="AR" term="%22Liebisch+G%2E%22">Liebisch G.</searchLink><br /><searchLink fieldCode="AR" term="%22Hesse+B%2E%22">Hesse B.</searchLink><br /><searchLink fieldCode="AR" term="%22Lukasz+A%2E+H%2E%22">Lukasz A. H.</searchLink><br /><searchLink fieldCode="AR" term="%22Rossaint+J%2E%22">Rossaint J.</searchLink><br /><searchLink fieldCode="AR" term="%22Kehrel+B%2E+E%2E%22">Kehrel B. E.</searchLink><br /><searchLink fieldCode="AR" term="%22Rosenbauer+F%2E%22">Rosenbauer F.</searchLink><br /><searchLink fieldCode="AR" term="%22Renne+T%2E%22">Renne T.</searchLink><br /><searchLink fieldCode="AR" term="%22Christoffersen+C%2E%22">Christoffersen C.</searchLink><br /><searchLink fieldCode="AR" term="%22Simoni+M%2E%22">Simoni M.</searchLink><br /><searchLink fieldCode="AR" term="%22Burkhardt+R%2E%22">Burkhardt R.</searchLink><br /><searchLink fieldCode="AR" term="%22Nofer+J%2E+-R%2E%22">Nofer J. -R.</searchLink>
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  Label: Contributors
  Group: Au
  Data: Poti, F.<br />Scalera, E.<br />Feuerborn, R.<br />Fischer, J.<br />Arndt, L.<br />Varga, G.<br />Pardali, E.<br />Seidl, M. D.<br />Fobker, M.<br />Liebisch, G.<br />Hesse, B.<br />Lukasz, A. H.<br />Rossaint, J.<br />Kehrel, B. E.<br />Rosenbauer, F.<br />Renne, T.<br />Christoffersen, C.<br />Simoni, M.<br />Burkhardt, R.<br />Nofer, J. -R.
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  Data: 2024
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  Data: Archivio della ricerca dell'Università di Modena e Reggio Emilia (Unimore: IRIS)
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  Data: <searchLink fieldCode="DE" term="%22Atherosclerosi%22">Atherosclerosi</searchLink><br /><searchLink fieldCode="DE" term="%22Inflammation%22">Inflammation</searchLink><br /><searchLink fieldCode="DE" term="%22Lipoprotein%22">Lipoprotein</searchLink><br /><searchLink fieldCode="DE" term="%22Macrophage%22">Macrophage</searchLink><br /><searchLink fieldCode="DE" term="%22Vascular+biology%22">Vascular biology</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: Sphingosine 1-phosphate (S1P) is a lysosphingolipid with antiatherogenic properties, but mechanisms underlying its effects remain unclear. We here investigated atherosclerosis development in cholesterol-rich diet–fed LDL receptor–deficient mice with high or low overexpression levels of S1P receptor 1 (S1P1) in macrophages. S1P1-overexpressing macrophages showed increased activity of transcription factors PU.1, interferon regulatory factor 8 (IRF8), and liver X receptor (LXR) and were skewed toward an M2-distinct phenotype characterized by enhanced production of IL-10, IL-1RA, and IL-5; increased ATP-binding cassette transporter A1– and G1–dependent cholesterol efflux; increased expression of MerTK and efferocytosis; and reduced apoptosis due to elevated B cell lymphoma 6 and Maf bZIP B. A similar macrophage phenotype was observed in mice administered S1P1-selective agonist KRP203. Mechanistically, the enhanced PU.1, IRF8, and LXR activity in S1P1-overexpressing macrophages led to downregulation of the cAMP-dependent PKA and activation of the signaling cascade encompassing protein kinases AKT and mTOR complex 1 as well as the late endosomal/lysosomal adaptor MAPK and mTOR activator 1. Atherosclerotic lesions in aortic roots and brachiocephalic arteries were profoundly or moderately reduced in mice with high and low S1P1 overexpression in macrophages, respectively. We conclude that S1P1 signaling polarizes macrophages toward an antiatherogenic functional phenotype and countervails the development of atherosclerosis in mice.
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  Data: info:eu-repo/semantics/altIdentifier/pmid/39531328; info:eu-repo/semantics/altIdentifier/wos/WOS:001381847200001; volume:9; issue:24; firstpage:N/A; lastpage:N/A; journal:JCI INSIGHT; https://hdl.handle.net/11380/1373952
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1172/jci.insight.158127
– Name: URL
  Label: Availability
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  Data: https://hdl.handle.net/11380/1373952<br />https://doi.org/10.1172/jci.insight.158127
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  Data: info:eu-repo/semantics/openAccess ; license:[IR] creative-commons ; license uri:http://creativecommons.org/licenses/by/4.0/
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