Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice

Christine Koulis, Yung-Chih Chen, Christian Hausding, Ingo Ahrens, Tin Soe Kyaw, Christopher Tay, Terri J Allen, Karin Agnes Maria Jandeleit-Dahm, Matthew James Sweet, Shizuo Akira, Alexander Bobik, Karlheinz Peter, Alexander Agrotis

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42 Citations (Scopus)

Abstract

OBJECTIVE - : Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9-/- has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE -/-) mice. APPROACH AND RESULTS - : Newly generated double-knockout ApoE-/-:TLR9-/- mice and control ApoE-/- mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE-/-:TLR9-/- mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 T cells. Although ApoE-/-:TLR9-/- mice exhibited an increase in plasma very low-density lipoprotein/low-density- lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE-/-:TLR9 -/- mice, CD4 T-cell accumulation was further investigated and depletion of these cells in ApoE-/-:TLR9-/- mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9-/- agonist (type B CpG oligodeoxynucleotide 1668) to ApoE-/- mice resulted in a reduction of lesion severity. CONCLUSIONS - : Genetic deletion of the innate immune receptor TLR9 -/- exacerbated atherosclerosis in ApoE-/- mice fed a high-fat diet. CD4 T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9-/- agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis. ? 2013 American Heart Association, Inc.
Original languageEnglish
Pages (from-to)516 - 525
Number of pages10
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume34
Issue number3
DOIs
Publication statusPublished - 2014

Cite this

Koulis, Christine ; Chen, Yung-Chih ; Hausding, Christian ; Ahrens, Ingo ; Kyaw, Tin Soe ; Tay, Christopher ; Allen, Terri J ; Jandeleit-Dahm, Karin Agnes Maria ; Sweet, Matthew James ; Akira, Shizuo ; Bobik, Alexander ; Peter, Karlheinz ; Agrotis, Alexander. / Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice. In: Arteriosclerosis, Thrombosis and Vascular Biology. 2014 ; Vol. 34, No. 3. pp. 516 - 525.
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title = "Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice",
abstract = "OBJECTIVE - : Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9-/- has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE -/-) mice. APPROACH AND RESULTS - : Newly generated double-knockout ApoE-/-:TLR9-/- mice and control ApoE-/- mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE-/-:TLR9-/- mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 T cells. Although ApoE-/-:TLR9-/- mice exhibited an increase in plasma very low-density lipoprotein/low-density- lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE-/-:TLR9 -/- mice, CD4 T-cell accumulation was further investigated and depletion of these cells in ApoE-/-:TLR9-/- mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9-/- agonist (type B CpG oligodeoxynucleotide 1668) to ApoE-/- mice resulted in a reduction of lesion severity. CONCLUSIONS - : Genetic deletion of the innate immune receptor TLR9 -/- exacerbated atherosclerosis in ApoE-/- mice fed a high-fat diet. CD4 T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9-/- agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis. ? 2013 American Heart Association, Inc.",
author = "Christine Koulis and Yung-Chih Chen and Christian Hausding and Ingo Ahrens and Kyaw, {Tin Soe} and Christopher Tay and Allen, {Terri J} and Jandeleit-Dahm, {Karin Agnes Maria} and Sweet, {Matthew James} and Shizuo Akira and Alexander Bobik and Karlheinz Peter and Alexander Agrotis",
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Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice. / Koulis, Christine; Chen, Yung-Chih; Hausding, Christian; Ahrens, Ingo; Kyaw, Tin Soe; Tay, Christopher; Allen, Terri J; Jandeleit-Dahm, Karin Agnes Maria; Sweet, Matthew James; Akira, Shizuo; Bobik, Alexander; Peter, Karlheinz; Agrotis, Alexander.

In: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 34, No. 3, 2014, p. 516 - 525.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Protective role for Toll-like receptor-9 in the development of atherosclerosis in apolipoprotein E-deficient mice

AU - Koulis, Christine

AU - Chen, Yung-Chih

AU - Hausding, Christian

AU - Ahrens, Ingo

AU - Kyaw, Tin Soe

AU - Tay, Christopher

AU - Allen, Terri J

AU - Jandeleit-Dahm, Karin Agnes Maria

AU - Sweet, Matthew James

AU - Akira, Shizuo

AU - Bobik, Alexander

AU - Peter, Karlheinz

AU - Agrotis, Alexander

PY - 2014

Y1 - 2014

N2 - OBJECTIVE - : Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9-/- has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE -/-) mice. APPROACH AND RESULTS - : Newly generated double-knockout ApoE-/-:TLR9-/- mice and control ApoE-/- mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE-/-:TLR9-/- mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 T cells. Although ApoE-/-:TLR9-/- mice exhibited an increase in plasma very low-density lipoprotein/low-density- lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE-/-:TLR9 -/- mice, CD4 T-cell accumulation was further investigated and depletion of these cells in ApoE-/-:TLR9-/- mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9-/- agonist (type B CpG oligodeoxynucleotide 1668) to ApoE-/- mice resulted in a reduction of lesion severity. CONCLUSIONS - : Genetic deletion of the innate immune receptor TLR9 -/- exacerbated atherosclerosis in ApoE-/- mice fed a high-fat diet. CD4 T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9-/- agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis. ? 2013 American Heart Association, Inc.

AB - OBJECTIVE - : Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9-/- has a role in the development of atherosclerosis in apolipoprotein E-deficient (ApoE -/-) mice. APPROACH AND RESULTS - : Newly generated double-knockout ApoE-/-:TLR9-/- mice and control ApoE-/- mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE-/-:TLR9-/- mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4 T cells. Although ApoE-/-:TLR9-/- mice exhibited an increase in plasma very low-density lipoprotein/low-density- lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE-/-:TLR9 -/- mice, CD4 T-cell accumulation was further investigated and depletion of these cells in ApoE-/-:TLR9-/- mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9-/- agonist (type B CpG oligodeoxynucleotide 1668) to ApoE-/- mice resulted in a reduction of lesion severity. CONCLUSIONS - : Genetic deletion of the innate immune receptor TLR9 -/- exacerbated atherosclerosis in ApoE-/- mice fed a high-fat diet. CD4 T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9-/- agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis. ? 2013 American Heart Association, Inc.

UR - http://atvb.ahajournals.org/content/34/3/516.full.pdf+html

U2 - 10.1161/ATVBAHA.113.302407

DO - 10.1161/ATVBAHA.113.302407

M3 - Article

VL - 34

SP - 516

EP - 525

JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

SN - 1079-5642

IS - 3

ER -