Macrophage heterogeneity in cardiometabolic disease

Abstract Metabolic diseases such as obesity and atherosclerosis are characterised by chronic inflammation that leads to the accumulation of immune cells in affected organs. Macrophages in the obese adipose tissue and the atherosclerotic plaque show transcriptional, phenotypic and functional heterogeneity. The accumulation of CD11c+ macrophages in atherosclerosis and obesity suggests the presence of conserved macrophage phenotypes in metabolic tissues. We aimed to characterise shared and distinct features of monocytes and macrophages in the aorta and adipose tissue in the context of metabolic disease using single-cell techniques. Single-cell RNA sequencing of the blood, aorta and visceral adipose tissue during a time course of metabolic disease progression (steady state, 12w western diet, 18w western diet) and data integration with murine aortic and adipose tissue community datasets revealed conserved and tissue specific features of metabolic disease. Resident macrophages in the aorta and adipose tissue displayed tissue specific transcriptional programs, highlighting that cell maintenance and function of tissue resident macrophages differ between metabolic tissues. Further, macrophages in the aorta and adipose tissue undergo disease associated compositional changes. For example, we uncovered distinct CD11c+ macrophage subsets that are conserved in the aorta and adipose tissue across multiple metabolic disease models and share core transcriptional signatures between both metabolic tissues. However, CD11c+ macrophage subsets showed tissue specific dynamics during metabolic disease progression. Overall, our analysis underscores that tissue niche affects macrophage composition as well as activation and transcriptional regulation patterns. Understanding similarities and differences between the two tissues will be important to inform identification of new therapeutic targets for cardiometabolic diseases.