IL-2Rβγ signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice

Megan Mulholland; Gabriel Jakobsson; Yu Lei; Lena Sundius; Irena Ljungcrantz; Sara Rattik; Uwe J F Tietge; Daniel Engelbertsen

doi:10.1016/j.atherosclerosis.2021.04.010

IL-2Rβγ signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice

Megan Mulholland, Gabriel Jakobsson, Yu Lei, Lena Sundius, Irena Ljungcrantz, Sara Rattik, Uwe J F Tietge, Daniel Engelbertsen

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

Abstract

BACKGROUND AND AIMS: The relationship between inflammation and lipid metabolism is complex and bidirectional. Lymphocyte-driven inflammation has been shown to modulate both atherosclerotic plaque development and cholesterol levels, but the mechanisms are incompletely understood.

METHODS: The cardiometabolic effects of IL-2Rβγ signalling in atherosclerotic Apoe-/- mice were investigated by treatment with an agonistic IL-2Rβγ-targeting IL-2/anti-IL-2 complex or a monoclonal anti-CD122 (IL-2Rβ) blocking antibody.

RESULTS: Administration of IL-2Rβγ agonistic IL-2/anti-IL-2 complexes to Apoe-/- mice augmented opposing arms of the adaptive immune system. Expansion of effector/memory T cells and increased levels of circulating pro-inflammatory cytokines were observed along with elevated levels of regulatory T cells and IL-10. Notably, IL-2/anti-IL-2 treatment did not affect plaque size but decreased levels of plasma cholesterol. The cholesterol lowering effect of IL-2Rβγ agonism was not affected by anti-CD8 or anti-NK1.1 depleting antibody treatment but was contingent on the presence of adaptive immunity. Expression of multiple liver X receptor (LXR)-related genes, including Pltp and Srebp1c in the liver, was decreased by IL-2/anti-IL-2 treatment. Although IL-2Rβγ agonism lowered cholesterol levels, blocking IL-2Rβγ signalling using an anti-CD122 monoclonal antibody did not impact cholesterol levels or plaque burden in Apoe-/- mice.

CONCLUSIONS: Elevated IL-2Rβγ signalling results in activation of both inflammatory and regulatory lymphocytes with a net zero effect on atherosclerosis and decreased plasma cholesterol levels. Changes in cholesterol levels were associated with reductions in hepatic LXR-related gene expression. Further studies are needed to investigate the clinical significance of IL-2 mediated modulation of hepatic LXR signalling in inflammatory disorders.

Original language	English
Pages (from-to)	1-10
Number of pages	10
Journal	Atherosclerosis
Volume	326
Early online date	2021 Apr 24
DOIs	https://doi.org/10.1016/j.atherosclerosis.2021.04.010
Publication status	Published - 2021 Jun 1

Subject classification (UKÄ)

Cardiac and Cardiovascular Systems
Cell and Molecular Biology

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1 Doctoral Thesis (compilation)

Regulation of T cells in Atherosclerosis
Mulholland, M., 2023, Lund: Lund University, Faculty of Medicine. 117 p.
Research output: Thesis › Doctoral Thesis (compilation)

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title = "IL-2Rβγ signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice",

abstract = "BACKGROUND AND AIMS: The relationship between inflammation and lipid metabolism is complex and bidirectional. Lymphocyte-driven inflammation has been shown to modulate both atherosclerotic plaque development and cholesterol levels, but the mechanisms are incompletely understood.METHODS: The cardiometabolic effects of IL-2Rβγ signalling in atherosclerotic Apoe-/- mice were investigated by treatment with an agonistic IL-2Rβγ-targeting IL-2/anti-IL-2 complex or a monoclonal anti-CD122 (IL-2Rβ) blocking antibody.RESULTS: Administration of IL-2Rβγ agonistic IL-2/anti-IL-2 complexes to Apoe-/- mice augmented opposing arms of the adaptive immune system. Expansion of effector/memory T cells and increased levels of circulating pro-inflammatory cytokines were observed along with elevated levels of regulatory T cells and IL-10. Notably, IL-2/anti-IL-2 treatment did not affect plaque size but decreased levels of plasma cholesterol. The cholesterol lowering effect of IL-2Rβγ agonism was not affected by anti-CD8 or anti-NK1.1 depleting antibody treatment but was contingent on the presence of adaptive immunity. Expression of multiple liver X receptor (LXR)-related genes, including Pltp and Srebp1c in the liver, was decreased by IL-2/anti-IL-2 treatment. Although IL-2Rβγ agonism lowered cholesterol levels, blocking IL-2Rβγ signalling using an anti-CD122 monoclonal antibody did not impact cholesterol levels or plaque burden in Apoe-/- mice.CONCLUSIONS: Elevated IL-2Rβγ signalling results in activation of both inflammatory and regulatory lymphocytes with a net zero effect on atherosclerosis and decreased plasma cholesterol levels. Changes in cholesterol levels were associated with reductions in hepatic LXR-related gene expression. Further studies are needed to investigate the clinical significance of IL-2 mediated modulation of hepatic LXR signalling in inflammatory disorders.",

author = "Megan Mulholland and Gabriel Jakobsson and Yu Lei and Lena Sundius and Irena Ljungcrantz and Sara Rattik and Tietge, {Uwe J F} and Daniel Engelbertsen",

year = "2021",

month = jun,

day = "1",

doi = "10.1016/j.atherosclerosis.2021.04.010",

language = "English",

volume = "326",

pages = "1--10",

journal = "Atherosclerosis",

issn = "1879-1484",

publisher = "Elsevier",

}

TY - JOUR

T1 - IL-2Rβγ signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice

AU - Mulholland, Megan

AU - Jakobsson, Gabriel

AU - Lei, Yu

AU - Sundius, Lena

AU - Ljungcrantz, Irena

AU - Rattik, Sara

AU - Tietge, Uwe J F

AU - Engelbertsen, Daniel

PY - 2021/6/1

Y1 - 2021/6/1

N2 - BACKGROUND AND AIMS: The relationship between inflammation and lipid metabolism is complex and bidirectional. Lymphocyte-driven inflammation has been shown to modulate both atherosclerotic plaque development and cholesterol levels, but the mechanisms are incompletely understood.METHODS: The cardiometabolic effects of IL-2Rβγ signalling in atherosclerotic Apoe-/- mice were investigated by treatment with an agonistic IL-2Rβγ-targeting IL-2/anti-IL-2 complex or a monoclonal anti-CD122 (IL-2Rβ) blocking antibody.RESULTS: Administration of IL-2Rβγ agonistic IL-2/anti-IL-2 complexes to Apoe-/- mice augmented opposing arms of the adaptive immune system. Expansion of effector/memory T cells and increased levels of circulating pro-inflammatory cytokines were observed along with elevated levels of regulatory T cells and IL-10. Notably, IL-2/anti-IL-2 treatment did not affect plaque size but decreased levels of plasma cholesterol. The cholesterol lowering effect of IL-2Rβγ agonism was not affected by anti-CD8 or anti-NK1.1 depleting antibody treatment but was contingent on the presence of adaptive immunity. Expression of multiple liver X receptor (LXR)-related genes, including Pltp and Srebp1c in the liver, was decreased by IL-2/anti-IL-2 treatment. Although IL-2Rβγ agonism lowered cholesterol levels, blocking IL-2Rβγ signalling using an anti-CD122 monoclonal antibody did not impact cholesterol levels or plaque burden in Apoe-/- mice.CONCLUSIONS: Elevated IL-2Rβγ signalling results in activation of both inflammatory and regulatory lymphocytes with a net zero effect on atherosclerosis and decreased plasma cholesterol levels. Changes in cholesterol levels were associated with reductions in hepatic LXR-related gene expression. Further studies are needed to investigate the clinical significance of IL-2 mediated modulation of hepatic LXR signalling in inflammatory disorders.

AB - BACKGROUND AND AIMS: The relationship between inflammation and lipid metabolism is complex and bidirectional. Lymphocyte-driven inflammation has been shown to modulate both atherosclerotic plaque development and cholesterol levels, but the mechanisms are incompletely understood.METHODS: The cardiometabolic effects of IL-2Rβγ signalling in atherosclerotic Apoe-/- mice were investigated by treatment with an agonistic IL-2Rβγ-targeting IL-2/anti-IL-2 complex or a monoclonal anti-CD122 (IL-2Rβ) blocking antibody.RESULTS: Administration of IL-2Rβγ agonistic IL-2/anti-IL-2 complexes to Apoe-/- mice augmented opposing arms of the adaptive immune system. Expansion of effector/memory T cells and increased levels of circulating pro-inflammatory cytokines were observed along with elevated levels of regulatory T cells and IL-10. Notably, IL-2/anti-IL-2 treatment did not affect plaque size but decreased levels of plasma cholesterol. The cholesterol lowering effect of IL-2Rβγ agonism was not affected by anti-CD8 or anti-NK1.1 depleting antibody treatment but was contingent on the presence of adaptive immunity. Expression of multiple liver X receptor (LXR)-related genes, including Pltp and Srebp1c in the liver, was decreased by IL-2/anti-IL-2 treatment. Although IL-2Rβγ agonism lowered cholesterol levels, blocking IL-2Rβγ signalling using an anti-CD122 monoclonal antibody did not impact cholesterol levels or plaque burden in Apoe-/- mice.CONCLUSIONS: Elevated IL-2Rβγ signalling results in activation of both inflammatory and regulatory lymphocytes with a net zero effect on atherosclerosis and decreased plasma cholesterol levels. Changes in cholesterol levels were associated with reductions in hepatic LXR-related gene expression. Further studies are needed to investigate the clinical significance of IL-2 mediated modulation of hepatic LXR signalling in inflammatory disorders.

U2 - 10.1016/j.atherosclerosis.2021.04.010

DO - 10.1016/j.atherosclerosis.2021.04.010

M3 - Article

C2 - 33945906

SN - 1879-1484

VL - 326

SP - 1

EP - 10

JO - Atherosclerosis

JF - Atherosclerosis

ER -

IL-2Rβγ signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice

Abstract

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Research output

Regulation of T cells in Atherosclerosis

Cite this