Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression

Abstract

Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DC) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aorta intima resident macrophages (Mac AIR ) that depend upon Csf-1 and sustained by local proliferation. Although Mac AIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaque is overtaken by recruited monocytes, which induce Mac AIR -defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.

Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering

“…Whether these embryonically derived macrophages in the adventitia directly contribute to macrophages accumulating in intimal lesions is unknown. A small population of intima resident macrophages shows limited proliferation capacity and is marginalized during plaque progression [68] as monocytes infiltrate giving rise to proliferating macrophages [49]. Atorvastatin fails to induce plaque regression without cholesterol lowering in Apoe -/mice.…”

Monocyte Recruitment, Specification, and Function in Atherosclerosis

“…These cells are maintained in the tissue by local proliferation through the lifespan of the mouse. Furthermore, aorta-intima-resident macrophages (Mac AIR ) reside in the aorta and derive from monocytes after birth [ 66 , 67 , 68 ]. Mac AIR are the first population of foamy macrophages that can be detected within a week of high fat/high cholesterol feeding [ 66 , 69 ].…”

“…Furthermore, aorta-intima-resident macrophages (Mac AIR ) reside in the aorta and derive from monocytes after birth [ 66 , 67 , 68 ]. Mac AIR are the first population of foamy macrophages that can be detected within a week of high fat/high cholesterol feeding [ 66 , 69 ]. Following high fat/high cholesterol feeding, these cells also promote the recruitment of monocytes to plaque [ 66 ].…”

LDL delivery of microbial small RNAs drives atherosclerosis through macrophage TLR8

“…Hence, we observed two resident macrophage clusters distinguishable by the expression of Bcell markers Cd79a, Ms4a1, Fcamr and Ighm (C1 vs C4), which may be the result of pre/pro-B cell differentiation to macrophages 63 . Aortic intimal resident macrophages (Mac-AIR; C9) were categorized by their expression of Cx3cr1 and Itgax, as well as genes in lipid metabolism (Abcg1, Scarb1, Pparg, Cebpb) 64 . Interestingly, this population also had selective expression of Cd300e, as well as enriched expression of Nr4a1, a transcription factor associated with resident macrophage differentiation 65 .…”