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 (DCs) 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 aortic intima resident macrophages (MacAIR) that depend upon colony-stimulating factor 1 and are sustained by local proliferation. Although MacAIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaques is overtaken by recruited monocytes, which induce MacAIR-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.
Bibliographical noteFunding Information:
Flt3Cre mice were provided by D. Mann (Washington University School of Medicine; WUSM); Flt3−/−, Flt3l−/−, SNZ22GFP, L-MycGFP and Zbtb46GFP mice were provided by K. Murphy (WUSM); IL-34−/− and CCR2GFP mice were provided by M. Colonna (WUSM); op/op mice were provided by E. Unanue (WUSM); and Csf2rb−/− mice were provided B. Edelson (WUSM). We also thank M. Vail (University of Minnesota), the WUSM Flow Cytometry Core Facility, WUSM McDonnell Genome Institute and WUSM Genome Technology Access Center for technical assistance on this study. Research was supported by the National Institutes of Health (NIH) R00 HL138163 (to J.W.W.), AHA 16SDGG30480008 (to B.H.Z.), T32 AI007313 (to C.G.T.), P01 AI35296 (to B.T.F.) and NIH R37 AI049653 and DP1DK109668 (to G.J.R.). J.W.W. was supported by NIH 2T32DK007120-41 and AHA 17POST33410473. J-H.C. was supported by the Korean Health Technology R&D project HI15C0399 and Ministry of Health, Welfare & Family Affairs (South Korea). K.Z. was supported by the Government of Russian Federation (grant no. 08-08).
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural
- Research Support, Non-U.S. Gov't