| First Author | Mulholland M | Year | 2021 |
| Journal | Atherosclerosis | Volume | 326 |
| Pages | 1-10 | PubMed ID | 33945906 |
| Mgi Jnum | J:312311 | Mgi Id | MGI:6740646 |
| Doi | 10.1016/j.atherosclerosis.2021.04.010 | Citation | Mulholland M, et al. (2021) IL-2Rbetagamma signalling in lymphocytes promotes systemic inflammation and reduces plasma cholesterol in atherosclerotic mice. Atherosclerosis 326:1-10 |
| abstractText | 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-2Rbetagamma signalling in atherosclerotic Apoe(-/-) mice were investigated by treatment with an agonistic IL-2Rbetagamma-targeting IL-2/anti-IL-2 complex or a monoclonal anti-CD122 (IL-2Rbeta) blocking antibody. RESULTS: Administration of IL-2Rbetagamma 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-2Rbetagamma 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-2Rbetagamma agonism lowered cholesterol levels, blocking IL-2Rbetagamma signalling using an anti-CD122 monoclonal antibody did not impact cholesterol levels or plaque burden in Apoe(-/-) mice. CONCLUSIONS: Elevated IL-2Rbetagamma 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. |
