Natural killer (NK) cells augment atherosclerosis by cytotoxic-dependent mechanisms

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Abstract

AIM: Although natural killer (NK) cells, a key component of the innate immune system, have been identified in human and mouse atherosclerotic lesions, their role in atherosclerosis development remains unclear. To determine their role in atherosclerosis, we used both loss- and gain-of-function experiments in ApoE(-/-) mice fed a high-fat diet. METHODS AND RESULTS: Treatment of ApoE(-/-) mice with anti-Asialo-GM1 antibodies depleted NK cells without affecting other lymphocytes, including natural killer T cells, and greatly attenuated atherosclerosis. These effects were independent of plasma lipids. To confirm the atherogenicity of NK cells, these cells were isolated from mouse spleens for adoptive transfer into lymphocyte-deficient ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice. Transfer of NK cells from wild-type mice into ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice doubled lesion size, confirming a pro-atherogenic role for NK cells. To determine whether their atherogenicity was dependent on production of interferon-gamma (IFN-gamma) or cytotoxins, we compared the transfer of NK cells deficient in IFN-gamma, perforin, and granzyme B with the transfer of wild-type NK cells. Transfer of IFN-gamma-deficient NK cells increased lesion size in the lymphocyte-deficient ApoE(-/-) mice as wild-type NK cells. However, granzyme B- and perforin-deficient NK cells did not affect lesion size. Only wild-type NK cells increased necrotic core size, whereas perforin- and granzyme B-deficient NK cells did not. Plasma lipid levels were largely unaffected by the cell transfer. CONCLUSION: Our loss- and gain-of-function findings provide definitive evidence that NK cells are atherogenic and their production of perforin and granzyme B contributes to atherosclerosis and the expansion of necrotic cores.
Original languageEnglish
Pages (from-to)128 - 137
Number of pages10
JournalCardiovascular Research
Volume102
Issue number1
DOIs
Publication statusPublished - 2014

Cite this

@article{7b493865746a4136afcb196c838581ab,
title = "Natural killer (NK) cells augment atherosclerosis by cytotoxic-dependent mechanisms",
abstract = "AIM: Although natural killer (NK) cells, a key component of the innate immune system, have been identified in human and mouse atherosclerotic lesions, their role in atherosclerosis development remains unclear. To determine their role in atherosclerosis, we used both loss- and gain-of-function experiments in ApoE(-/-) mice fed a high-fat diet. METHODS AND RESULTS: Treatment of ApoE(-/-) mice with anti-Asialo-GM1 antibodies depleted NK cells without affecting other lymphocytes, including natural killer T cells, and greatly attenuated atherosclerosis. These effects were independent of plasma lipids. To confirm the atherogenicity of NK cells, these cells were isolated from mouse spleens for adoptive transfer into lymphocyte-deficient ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice. Transfer of NK cells from wild-type mice into ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice doubled lesion size, confirming a pro-atherogenic role for NK cells. To determine whether their atherogenicity was dependent on production of interferon-gamma (IFN-gamma) or cytotoxins, we compared the transfer of NK cells deficient in IFN-gamma, perforin, and granzyme B with the transfer of wild-type NK cells. Transfer of IFN-gamma-deficient NK cells increased lesion size in the lymphocyte-deficient ApoE(-/-) mice as wild-type NK cells. However, granzyme B- and perforin-deficient NK cells did not affect lesion size. Only wild-type NK cells increased necrotic core size, whereas perforin- and granzyme B-deficient NK cells did not. Plasma lipid levels were largely unaffected by the cell transfer. CONCLUSION: Our loss- and gain-of-function findings provide definitive evidence that NK cells are atherogenic and their production of perforin and granzyme B contributes to atherosclerosis and the expansion of necrotic cores.",
author = "Ahrathy Selathurai and Virginie Deswaerte and Peter Kanellakis and Tipping, {Peter George} and Ban-Hock Toh and Alexander Bobik and Kyaw, {Tin Soe}",
year = "2014",
doi = "10.1093/cvr/cvu016",
language = "English",
volume = "102",
pages = "128 -- 137",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "1",

}

Natural killer (NK) cells augment atherosclerosis by cytotoxic-dependent mechanisms. / Selathurai, Ahrathy; Deswaerte, Virginie; Kanellakis, Peter; Tipping, Peter George; Toh, Ban-Hock; Bobik, Alexander; Kyaw, Tin Soe.

In: Cardiovascular Research, Vol. 102, No. 1, 2014, p. 128 - 137.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Natural killer (NK) cells augment atherosclerosis by cytotoxic-dependent mechanisms

AU - Selathurai, Ahrathy

AU - Deswaerte, Virginie

AU - Kanellakis, Peter

AU - Tipping, Peter George

AU - Toh, Ban-Hock

AU - Bobik, Alexander

AU - Kyaw, Tin Soe

PY - 2014

Y1 - 2014

N2 - AIM: Although natural killer (NK) cells, a key component of the innate immune system, have been identified in human and mouse atherosclerotic lesions, their role in atherosclerosis development remains unclear. To determine their role in atherosclerosis, we used both loss- and gain-of-function experiments in ApoE(-/-) mice fed a high-fat diet. METHODS AND RESULTS: Treatment of ApoE(-/-) mice with anti-Asialo-GM1 antibodies depleted NK cells without affecting other lymphocytes, including natural killer T cells, and greatly attenuated atherosclerosis. These effects were independent of plasma lipids. To confirm the atherogenicity of NK cells, these cells were isolated from mouse spleens for adoptive transfer into lymphocyte-deficient ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice. Transfer of NK cells from wild-type mice into ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice doubled lesion size, confirming a pro-atherogenic role for NK cells. To determine whether their atherogenicity was dependent on production of interferon-gamma (IFN-gamma) or cytotoxins, we compared the transfer of NK cells deficient in IFN-gamma, perforin, and granzyme B with the transfer of wild-type NK cells. Transfer of IFN-gamma-deficient NK cells increased lesion size in the lymphocyte-deficient ApoE(-/-) mice as wild-type NK cells. However, granzyme B- and perforin-deficient NK cells did not affect lesion size. Only wild-type NK cells increased necrotic core size, whereas perforin- and granzyme B-deficient NK cells did not. Plasma lipid levels were largely unaffected by the cell transfer. CONCLUSION: Our loss- and gain-of-function findings provide definitive evidence that NK cells are atherogenic and their production of perforin and granzyme B contributes to atherosclerosis and the expansion of necrotic cores.

AB - AIM: Although natural killer (NK) cells, a key component of the innate immune system, have been identified in human and mouse atherosclerotic lesions, their role in atherosclerosis development remains unclear. To determine their role in atherosclerosis, we used both loss- and gain-of-function experiments in ApoE(-/-) mice fed a high-fat diet. METHODS AND RESULTS: Treatment of ApoE(-/-) mice with anti-Asialo-GM1 antibodies depleted NK cells without affecting other lymphocytes, including natural killer T cells, and greatly attenuated atherosclerosis. These effects were independent of plasma lipids. To confirm the atherogenicity of NK cells, these cells were isolated from mouse spleens for adoptive transfer into lymphocyte-deficient ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice. Transfer of NK cells from wild-type mice into ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice doubled lesion size, confirming a pro-atherogenic role for NK cells. To determine whether their atherogenicity was dependent on production of interferon-gamma (IFN-gamma) or cytotoxins, we compared the transfer of NK cells deficient in IFN-gamma, perforin, and granzyme B with the transfer of wild-type NK cells. Transfer of IFN-gamma-deficient NK cells increased lesion size in the lymphocyte-deficient ApoE(-/-) mice as wild-type NK cells. However, granzyme B- and perforin-deficient NK cells did not affect lesion size. Only wild-type NK cells increased necrotic core size, whereas perforin- and granzyme B-deficient NK cells did not. Plasma lipid levels were largely unaffected by the cell transfer. CONCLUSION: Our loss- and gain-of-function findings provide definitive evidence that NK cells are atherogenic and their production of perforin and granzyme B contributes to atherosclerosis and the expansion of necrotic cores.

UR - http://cardiovascres.oxfordjournals.org/content/cardiovascres/102/1/128.full.pdf

U2 - 10.1093/cvr/cvu016

DO - 10.1093/cvr/cvu016

M3 - Article

VL - 102

SP - 128

EP - 137

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 1

ER -