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Daniel Engelbertsen

Assistant researcher

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

Author

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

Summary, in English

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.

Department/s

  • Department of Clinical Sciences, Malmö
  • Cardiovascular Research - Cellular Metabolism and Inflammation
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Cardiovascular Research - Translational Studies
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2021-06-01

Language

English

Pages

1-10

Publication/Series

Atherosclerosis

Volume

326

Document type

Journal article

Publisher

Elsevier

Topic

  • Cardiac and Cardiovascular Systems
  • Cell and Molecular Biology

Status

Published

Research group

  • Cardiovascular Research - Cellular Metabolism and Inflammation
  • Cardiovascular Research - Immunity and Atherosclerosis
  • Cardiovascular Research - Translational Studies

ISBN/ISSN/Other

  • ISSN: 1879-1484