Functional diversity of vascular macrophages in atherosclerosis

Atherosclerosis is a multifactorial chronic inflammatory disease of the artery. Diverse macrophage subsets in the atherosclerotic artery contribute to the pathogenesis of the disease. The dendritic cell immunoreceptor (DCIR) 1 is a C-type lectin receptor that inhibits immune responses in myeloid cells. DCIR1 plays both protective and detrimental roles in autoimmune diseases and pathogen-induced infections, respectively. However, to date, the role of DCIR1 in macrophage biology and atherosclerosis remains unknown. In this thesis, I identified six macrophage subsets by single cell technologies in the murine atherosclerotic aorta. These consist of three “resident” and three “recruited” subsets, which include two novel subpopulations (CD209b+ resident and CCR2+ recruited macrophages). DCIR1 is preferentially expressed by resident vascular macrophages and maintains the balance between resident and recruited macrophage subsets. A novel mouse strain LysMCre Dcir1-DTRflox enables ablation of vascular resident macrophages, together with the majority of tissue macrophages. DCIR1-mediated macrophage ablation opens the niche to Ly6C+ monocytes which can re-acquire DCIR1. This indicates that DCIR1 expression defines tissue resident macrophages. A comparative study using apolipoprotein E (ApoE)-/- and ApoE-/- Dcir1-/- mice showed that DCIR1 protects against atherosclerosis by maintaining the resident vascular macrophage niche in the aorta. The loss of DCIR1 alters the myeloid cell dynamics in the atherosclerotic aorta, promoting the recruitment of monocytes and macrophages and exacerbating disease evolution. In conclusion, DCIR1 is a potent regulator of myeloid homeostasis which acts to sustain the resident macrophage niche in the majority of organs. In atherosclerosis, DCIR1 alleviates the disease progression by sustaining the survival of two vascular resident macrophage subsets and limiting monocyte influx to the artery.