Exploring the Sex-Dependent Atheroprotective and Cardioprotective Roles of the IL-33/ILC2 Axis in a Dyslipidemia Mouse Model

Abstract

Atherosclerosis and maladaptive cardiac remodeling are highly prevalent cardiovascular conditions that often coexist, contributing to significant morbidity and mortality. Increasing evidence is suggesting that atherosclerosis and maladaptive cardiac remodeling are interconnected, sharing common pathophysiological mechanisms involving dyslipidemia, inflammation, oxidative stress and endothelial dysfunction. The IL-33/ILC2 axis has emerged as a key regulator of inflammation in the context of atherosclerosis and myocardial remodeling separately, yet no study has isolated the IL-33 effects mediated by ILC2 at the interconnection of these two diseases, nor explored whether the effects of this axis were sex-dependent. In this study, we aimed to investigate the sex-dependent contribution of ILC2s to the development of atherosclerosis and maladaptive cardiac remodeling and the atheroprotective and cardioprotective effects of exogenous IL-33 treatment mediated through ILC2 modulation using double knockout (DKO) mice deficient in low-density lipoprotein receptor (LDLR) and ILC2 signaling. Mice were subjected to a 60% high-fat diet for 12 weeks, and 1 μg IL-33 injections were administered twice a week. Our results demonstrated a sex-dependent role of ILC2 in modulating lipid metabolism and attenuating atherosclerosis in males. At the 12-week mark, the hearts of the mice showed no signs of remodeling, and consequently we could not assess the role of ILC2 in this aspect. Due to increased mortality following IL-33 administration, the study focused on identifying the underlying cause, which was consistent with an anaphylactic-like response. In conclusion, these findings highlight a sex-dependent role for ILC2 in atherosclerosis and underscore both the therapeutic potential and safety considerations of targeting the IL-33/ILC2 axis in cardiovascular disease.