Xcr1⁺ type 1 conventional dendritic cells are essential mediators for atherosclerosis progression.

Abstract

Atherosclerosis is characterized by lipid accumulation within plaques, leading to foam cell formation and an inflammatory response within the aortic lesions. Lipid disorders have been extensively investigated, however, the cellular and molecular mechanisms that trigger the inflammatory response in atherosclerotic plaques remain far from being fully understood. Xcr1⁺ cDC1 cells are newly identified antigen-presenting cells in activating immune cells. However, the role of cDC1 cells in atherosclerosis development remains highly controversial. We first confirmed the presence of cDC1 within human atherosclerotic plaques and discovered a significant association between the increasing cDC1 numbers and atherosclerosis progression in mice. Subsequently, we established <i>Xcr1^Cre-Gfp Rosa26^LSL-DTA Apoe^-/-</i> mice, a novel and complex genetic model, in which cDC1 was constitutively depleted in vivo during atherosclerosis development. Intriguingly, we observed a notable reduction in atherosclerotic lesions in hyperlipidemic mice, alongside suppressed T cell activation of both CD4⁺ and CD8⁺ subsets in the aortic plaques. Notably, aortic macrophages and serum lipid levels were not significantly changed in the cDC1-depleted mice. Single-cell RNA sequencing revealed heterogeneity of Xcr1⁺ cDC1 cells across the aorta and lymphoid organs under hyperlipidemic conditions. As Xcr1 is the sole receptor for Xcl1, we next explored to target Xcr1⁺ cDC1 cells via Xcl1 by establishing <i>Xcl1^-/-Apoe^-/-</i> mice. <i>Xcl1^-/-Apoe^-/-</i> mice exhibited decreased atherosclerotic plaque formation and reduced aortic cDC1 accumulation, indicating that Xcl1 contributes to cDC1-mediated atherosclerotic lesion development. Our results reveal crucial roles of cDC1 in atherosclerosis progression and provide insights into the development of immunotherapies by targeting cDC1 through Xcl1.