Leukemia inhibitory factor receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr−/− mice

Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhi...

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Published in:	European journal of pharmacology Vol. 985; p. 177121
Main Authors:	Hemme, Esmeralda, Depuydt, Marie A.C., van Santbrink, Peter J., Wezel, Anouk, Smeets, Harm J., Foks, Amanda C., Kuiper, Johan, Bot, Ilze
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 15.12.2024
Subjects:	Adhesion molecules Animals Atherosclerosis Atherosclerosis - drug therapy Atherosclerosis - metabolism Atherosclerosis - pathology Cholesterol Cytokines Endothelial Cells - drug effects Endothelial Cells - metabolism Female Humans Inflammation Leukemia inhibitory factor Leukemia Inhibitory Factor - genetics Leukemia Inhibitory Factor - metabolism Leukemia Inhibitory Factor Receptor alpha Subunit - genetics Leukemia Inhibitory Factor Receptor alpha Subunit - metabolism Mast Cells - drug effects Mast Cells - metabolism Mice Mice, Inbred C57BL Mice, Knockout Plaque, Atherosclerotic - drug therapy Receptors, LDL - deficiency Receptors, LDL - genetics Adhesion molecules Inflammation Cytokines Leukemia inhibitory factor Cholesterol Atherosclerosis
ISSN:	0014-2999, 1879-0712, 1879-0712
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Abstract	Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development. Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr−/− mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice. Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque. •LIFR/Lifr is expressed on activated endothelial cells in human and mouse plaques.•In human carotid plaques, LIF is almost exclusively expressed by mast cells.•EC359 treatment limits plaque development in Ldlr−/− mice.•LIF receptor inhibition reduces endothelial cell activation in vivo and in vitro.•EC359 treatment lowers total cholesterol levels in serum of Ldlr−/− mice.
AbstractList	Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development. Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice. Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque. Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development. Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr-/- mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice. Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development. Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr-/- mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice. Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque. Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development. Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express LIF, whereas LIFR was specifically expressed on activated endothelial cells. A similar expression pattern of Lifr was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed Ldlr−/− mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced Pecam1 and Vcam1 expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice. Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque. •LIFR/Lifr is expressed on activated endothelial cells in human and mouse plaques.•In human carotid plaques, LIF is almost exclusively expressed by mast cells.•EC359 treatment limits plaque development in Ldlr−/− mice.•LIF receptor inhibition reduces endothelial cell activation in vivo and in vitro.•EC359 treatment lowers total cholesterol levels in serum of Ldlr−/− mice.
ArticleNumber	177121
Author	Depuydt, Marie A.C. Kuiper, Johan Smeets, Harm J. Foks, Amanda C. van Santbrink, Peter J. Hemme, Esmeralda Wezel, Anouk Bot, Ilze
Author_xml	– sequence: 1 givenname: Esmeralda orcidid: 0000-0001-5853-8784 surname: Hemme fullname: Hemme, Esmeralda organization: Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands – sequence: 2 givenname: Marie A.C. orcidid: 0000-0002-7174-1952 surname: Depuydt fullname: Depuydt, Marie A.C. organization: Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands – sequence: 3 givenname: Peter J. surname: van Santbrink fullname: van Santbrink, Peter J. organization: Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands – sequence: 4 givenname: Anouk surname: Wezel fullname: Wezel, Anouk organization: Department of Surgery, Haaglanden Medical Center—location Westeinde, Lijnbaan 32, 2515, VA The Hague, the Netherlands – sequence: 5 givenname: Harm J. surname: Smeets fullname: Smeets, Harm J. organization: Department of Surgery, Haaglanden Medical Center—location Westeinde, Lijnbaan 32, 2515, VA The Hague, the Netherlands – sequence: 6 givenname: Amanda C. orcidid: 0000-0002-9747-3458 surname: Foks fullname: Foks, Amanda C. organization: Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands – sequence: 7 givenname: Johan surname: Kuiper fullname: Kuiper, Johan organization: Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands – sequence: 8 givenname: Ilze orcidid: 0000-0002-1242-1959 surname: Bot fullname: Bot, Ilze email: i.bot@lacdr.leidenuniv.nl organization: Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/39528103$$D View this record in MEDLINE/PubMed
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Keywords	Adhesion molecules Inflammation Cytokines Leukemia inhibitory factor Cholesterol Atherosclerosis
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Snippet	Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine...
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SubjectTerms	Adhesion molecules Animals Atherosclerosis Atherosclerosis - drug therapy Atherosclerosis - metabolism Atherosclerosis - pathology Cholesterol Cytokines Endothelial Cells - drug effects Endothelial Cells - metabolism Female Humans Inflammation Leukemia inhibitory factor Leukemia Inhibitory Factor - genetics Leukemia Inhibitory Factor - metabolism Leukemia Inhibitory Factor Receptor alpha Subunit - genetics Leukemia Inhibitory Factor Receptor alpha Subunit - metabolism Mast Cells - drug effects Mast Cells - metabolism Mice Mice, Inbred C57BL Mice, Knockout Plaque, Atherosclerotic - drug therapy Receptors, LDL - deficiency Receptors, LDL - genetics
Title	Leukemia inhibitory factor receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr−/− mice
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