Expansion of CD25 ⁺ Innate Lymphoid Cells Reduces Atherosclerosis

Abstract

Objective Innate lymphoid cells (ILCs) are a newly discovered subset of immune cells that promote tissue homeostasis and protect against pathogens. ILCs produce cytokines also produced by T lymphocytes that have been shown to affect atherosclerosis, but the influence of ILCs on atherosclerosis has not been explored. Approach and Results We demonstrate that CD25+ ILCs that produce type 2 cytokines (ILC2s) are present in the aorta of atherosclerotic immunodeficient ldlr−/−rag1−/− mice. To investigate the role of ILCs in atherosclerosis, ldlr−/−rag1−/− mice were concurrently fed an atherogenic diet and treated with either ILC-depleting anti-CD90.2 antibodies or with IL-2/anti-IL-2 complexes that expand CD25+ ILCs. Lesion development was not affected by anti-CD90.2 treatment, but was reduced in IL-2/anti-IL-2 -treated mice. These IL-2 treated mice had reduced VLDL cholesterol and increased triglycerides compared to controls and reduced apolipoprotein B100 gene expression in the liver. IL-2/anti-IL-2 treatment caused expansion of ILC2s in aorta and other tissues, elevated levels of IL-5, systemic eosinophila and hepatic eosinophilic inflammation. Blockade of IL-5 reversed the IL-2-complex-induced eosinophilia but did not change lesion size. Conclusions This study demonstrates that expansion of CD25-expressing ILCs by IL-2/anti-IL-2 complexes leads to a reduction in VLDL cholesterol and atherosclerosis. Global depletion of ILCs by anti-CD90.2 did not significantly affect lesion size indicating that different ILC subsets may have divergent effects on atherosclerosis.

Type-2 innate lymphoid cells control the development of atherosclerosis in mice

“…3B). However, as reported in previous work26, IL-2 treatment was not without a number of off-target effects, the most common of which was an increase in splenic fibrosis in the IL-2 treated group, which was severe in some mice (Supplementary Fig. 3C).…”

“…Previous studies suggested a potential role for ILC2 in the modulation of atherosclerosis2326. However, those studies used immune-compromised animals and relied on non-physiological exogenous and chronic administration of cytokines (that is, IL-2 and IL-25) that are not specific for the ILC2 population, and that can promote ILC2-independent immune responses.…”

Dendritic Cell KLF2 Expression Regulates T Cell Activation and Proatherogenic Immune Responses

“…Analysis of atherosclerotic lesion size was performed on 5 Oil-Red-O stained cryosections (10 μm each) spanning 160 μm of the three valve area of the aortic root, as described (28, 29). …”

Readapting the adaptive immune response – therapeutic strategies for atherosclerosis

“…One ‘side effect’ of this strategy is that IL‐2 may also expand CD25 + innate lymphoid cells. The role of these cells in atherosclerosis is just beginning to be investigated (Engelbertsen et al, ). Furthermore, there is incomplete knowledge on how IL‐2 therapy affects the emerging plasticity of Tregs (Butcher et al, ).…”