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

Atherosclerosis. 2021 Jun:326:1-10. doi: 10.1016/j.atherosclerosis.2021.04.010. Epub 2021 Apr 24.

Authors

Megan Mulholland¹, Gabriel Jakobsson², Yu Lei³, Lena Sundius², Irena Ljungcrantz², Sara Rattik², Uwe J F Tietge⁴, Daniel Engelbertsen⁵

Affiliations

¹ Department of Clinical Sciences, Lund University, Skåne University Hospital, 20502, Malmö, Sweden. Electronic address: megan.mulholland@med.lu.se.
² Department of Clinical Sciences, Lund University, Skåne University Hospital, 20502, Malmö, Sweden.
³ Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, S-14183, Stockholm, Sweden.
⁴ Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, S-14183, Stockholm, Sweden; Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, SE-141 86, Stockholm, Sweden.
⁵ Department of Clinical Sciences, Lund University, Skåne University Hospital, 20502, Malmö, Sweden. Electronic address: daniel.engelbertsen@med.lu.se.

PMID: 33945906
DOI: 10.1016/j.atherosclerosis.2021.04.010

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.

Keywords: Atherosclerosis; Cholesterol; Cytokines; IL-2; Inflammation; T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Atherosclerosis*
Cholesterol
Inflammation
Interleukin-2 Receptor beta Subunit*
Lymphocytes
Mice
Mice, Inbred C57BL
Mice, Knockout, ApoE
Plaque, Atherosclerotic*

Substances

Il2rb protein, mouse
Interleukin-2 Receptor beta Subunit
Cholesterol