The Role of IRG1 in Atherosclerosis

Atherosclerosis is a primary contributing factor to heart attacks and strokes which are the leading cause of death on a global scale. This disease is characterised by the accumulation of lipids and macrophages in the artery walls. Over the recent years, metabolism in macrophages gained increasing attention when it has been discovered that metabolic adaptation is central to cellular function. The immune responsive gene 1 (IRG1) is expressed in macrophages after a pro-inflammatory stimulus. The protein catalyses the synthesis of itaconate in the cell which influences certain metabolic pathways, reduces the production of reactive oxygen species and, promotes anti-inflammatory mechanism through activation of NRF2 and inhibition of the NLRP3 inflammasome. This thesis aims to understand the role of itaconate in inflammatory vascular diseases.
To study this question Irg1-/- mice were crossed with Apoe-/- or Ldlr-/- mice, two widely used atherosclerosis models. They were fed during 12 weeks with a high fat diet. Plaques are quantified in the aorta as well as the aortic root. Moreover, blood and spleen are further processed to characterize immune cells in presence or absence of Irg1. Bone marrow derived macrophages (BMDMs) are differentiated from the bone marrow of IRG1 deficient mice and are metabolically profiled to further understand the mechanism induced by itaconate in macrophages.
The plaque size in the aorta was reduced in female ApoE IRG1 deficient mice compared to their IRG1 wild-type (WT) littermates. However, the plaque size in the aortic valve was similar. Interestingly, LDLr IRG1 deficient male mice showed an increased body weight gain as well as an increased plasma cholesterol concentration. The immune cell profiling demonstrated that IRG1 deficiency influences T cells, especially in female mice in both atherosclerotic models. The BMDM study highlights metabolic changes induced by itaconate which are exacerbated if the cells are stimulated with lipopolysaccharide and interferon-gamma, both relevant stimuli in atherosclerosis.
Taken together this study supports the involvement of IRG1 in atherosclerosis and highlights the IRG1-induced metabolic rewiring in pro-inflammatory macrophages. Gaining a better understanding on the role of Irg1 in context of atherosclerosis may help for developing novel therapeutic strategies aiming to reduce inflammation and plaque size thereby reducing the incidence of cardiovascular events.