IL-2Rβγ signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice
(2021) In Atherosclerosis 326. p.1-10- 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... (More)
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.
(Less)
- author
- Mulholland, Megan LU ; Jakobsson, Gabriel LU ; Lei, Yu ; Sundius, Lena LU ; Ljungcrantz, Irena LU ; Rattik, Sara LU ; Tietge, Uwe J F and Engelbertsen, Daniel LU
- organization
- publishing date
- 2021-06-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Atherosclerosis
- volume
- 326
- pages
- 10 pages
- publisher
- Elsevier
- external identifiers
-
- scopus:85107902341
- pmid:33945906
- ISSN
- 1879-1484
- DOI
- 10.1016/j.atherosclerosis.2021.04.010
- language
- English
- LU publication?
- yes
- id
- b0f1a0be-1659-49a2-9ae9-dd1f07c1a057
- date added to LUP
- 2021-05-06 09:20:15
- date last changed
- 2025-04-06 15:45:16
@article{b0f1a0be-1659-49a2-9ae9-dd1f07c1a057,
abstract = {{<p>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.</p><p>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.</p><p>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.</p><p>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.</p>}},
author = {{Mulholland, Megan and Jakobsson, Gabriel and Lei, Yu and Sundius, Lena and Ljungcrantz, Irena and Rattik, Sara and Tietge, Uwe J F and Engelbertsen, Daniel}},
issn = {{1879-1484}},
language = {{eng}},
month = {{06}},
pages = {{1--10}},
publisher = {{Elsevier}},
series = {{Atherosclerosis}},
title = {{IL-2Rβγ signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice}},
url = {{http://dx.doi.org/10.1016/j.atherosclerosis.2021.04.010}},
doi = {{10.1016/j.atherosclerosis.2021.04.010}},
volume = {{326}},
year = {{2021}},
}