TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis

Siân P. Cartland; Scott W. Genner; Gonzalo J. Martínez; Stacy Robertson; Maaike Kockx; Ruby C. Y. Lin; John F. O'Sullivan; Yen Chin Koay; Pradeep Manuneedhi Cholan; Melkam A. Kebede; Andrew J. Murphy; Seth Masters; Martin R. Bennett; Wendy Jessup; Leonard Kritharides; Carolyn Geczy; Sanjay Patel; Mary M. Kavurma

doi:10.1016/j.isci.2018.12.037

TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis

Siân P. Cartland, Scott W. Genner, Gonzalo J. Martínez, Stacy Robertson, Maaike Kockx, Ruby C. Y. Lin, John F. O'Sullivan, Yen Chin Koay, Pradeep Manuneedhi Cholan, Melkam A. Kebede, Andrew J. Murphy, Seth Masters, Martin R. Bennett, Wendy Jessup, Leonard Kritharides, Carolyn Geczy, Sanjay Patel, Mary M. Kavurma^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

Original language	English
Pages (from-to)	41-52
Number of pages	26
Journal	iScience
Volume	12
DOIs	https://doi.org/10.1016/j.isci.2018.12.037
Publication status	Published - 22 Feb 2019
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

Diabetology
Immune Response
Immunology
Molecular Mechanism of Behavior
Pathophysiology

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10.1016/j.isci.2018.12.037Licence: CC BY-NC-ND

Publisher version (open access)Final published version, 2.39 MBLicence: CC BY-NC-ND

Cite this

Cartland, S. P., Genner, S. W., Martínez, G. J., Robertson, S., Kockx, M., Lin, R. C. Y., O'Sullivan, J. F., Koay, Y. C., Manuneedhi Cholan, P., Kebede, M. A., Murphy, A. J., Masters, S., Bennett, M. R., Jessup, W., Kritharides, L., Geczy, C., Patel, S., & Kavurma, M. M. (2019). TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis. iScience, 12, 41-52. https://doi.org/10.1016/j.isci.2018.12.037

@article{90a7f121420a433ea21278b9ecc22c9e,

title = "TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis",

abstract = "Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.",

keywords = "Diabetology, Immune Response, Immunology, Molecular Mechanism of Behavior, Pathophysiology",

author = "Cartland, {Si{\^a}n P.} and Genner, {Scott W.} and Mart{\'i}nez, {Gonzalo J.} and Stacy Robertson and Maaike Kockx and Lin, {Ruby C. Y.} and O'Sullivan, {John F.} and Koay, {Yen Chin} and {Manuneedhi Cholan}, Pradeep and Kebede, {Melkam A.} and Murphy, {Andrew J.} and Seth Masters and Bennett, {Martin R.} and Wendy Jessup and Leonard Kritharides and Carolyn Geczy and Sanjay Patel and Kavurma, {Mary M.}",

note = "Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2019",

month = feb,

day = "22",

doi = "10.1016/j.isci.2018.12.037",

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Cartland, SP, Genner, SW, Martínez, GJ, Robertson, S, Kockx, M, Lin, RCY, O'Sullivan, JF, Koay, YC, Manuneedhi Cholan, P, Kebede, MA, Murphy, AJ, Masters, S, Bennett, MR, Jessup, W, Kritharides, L, Geczy, C, Patel, S & Kavurma, MM 2019, 'TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis', iScience, vol. 12, pp. 41-52. https://doi.org/10.1016/j.isci.2018.12.037

TY - JOUR

T1 - TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis

AU - Cartland, Siân P.

AU - Genner, Scott W.

AU - Martínez, Gonzalo J.

AU - Robertson, Stacy

AU - Kockx, Maaike

AU - Lin, Ruby C. Y.

AU - O'Sullivan, John F.

AU - Koay, Yen Chin

AU - Manuneedhi Cholan, Pradeep

AU - Kebede, Melkam A.

AU - Murphy, Andrew J.

AU - Masters, Seth

AU - Bennett, Martin R.

AU - Jessup, Wendy

AU - Kritharides, Leonard

AU - Geczy, Carolyn

AU - Patel, Sanjay

AU - Kavurma, Mary M.

N1 - Copyright the Author(s) 2019. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2019/2/22

Y1 - 2019/2/22

N2 - Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

AB - Circulating tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) levels are reduced in patients with cardiovascular disease, and TRAIL gene deletion in mice exacerbates atherosclerosis and inflammation. How TRAIL protects against atherosclerosis and why levels are reduced in disease is unknown. Here, multiple strategies were used to identify the protective source of TRAIL and its mechanism(s) of action. Samples from patients with coronary artery disease and bone-marrow transplantation experiments in mice lacking TRAIL revealed monocytes/macrophages as the main protective source. Accordingly, deletion of TRAIL caused a more inflammatory macrophage with reduced migration, displaying impaired reverse cholesterol efflux and efferocytosis. Furthermore, interleukin (IL)-18, commonly increased in plasma of patients with cardiovascular disease, negatively regulated TRAIL transcription and gene expression, revealing an IL-18-TRAIL axis. These findings demonstrate that TRAIL is protective of atherosclerosis by modulating monocyte/macrophage phenotype and function. Manipulating TRAIL levels in these cells highlights a different therapeutic avenue in the treatment of cardiovascular disease.

KW - Diabetology

KW - Immune Response

KW - Immunology

KW - Molecular Mechanism of Behavior

KW - Pathophysiology

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U2 - 10.1016/j.isci.2018.12.037

DO - 10.1016/j.isci.2018.12.037

M3 - Article

C2 - 30665196

SN - 2589-0042

VL - 12

SP - 41

EP - 52

JO - iScience

JF - iScience

ER -

TRAIL-expressing monocyte/macrophages are critical for reducing inflammation and atherosclerosis

Abstract

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Keywords

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