Early events in atherosclerosis occur in the aortic intima and involve monocytes that become macrophages. We looked for these cells in the steady state adult mouse aorta, and surprisingly, we found a dominance of dendritic cells (DCs) in the intima. In contrast to aortic adventitial macrophages, CD11c +MHC II hi DCs were poorly phagocytic but were immune stimulatory. DCs were of two types primarily: classical Flt3-Flt3L signaling-dependent, CD103 +CD11b - DCs and macrophage-colony stimulating factor (M-CSF)-dependent, CD14 +CD11b +DC-SIGN + monocyte-derived DCs. Both types expanded during atherosclerosis. By crossing Flt3 -/- to Ldlr -/- atherosclerosis-prone mice, we developed a selective and marked deficiency of classical CD103 + aortic DCs, and they were associated with exacerbated atherosclerosis without alterations in blood lipids. Concomitantly, the Flt3 -/-Ldlr -/- mice had fewer Foxp3 + Treg cells and increased inflammatory cytokine mRNAs in the aorta. Therefore, functional DCs are dominant in normal aortic intima and, in contrast to macrophages, CD103 + classical DCs are associated with atherosclerosis protection.
Bibliographical noteFunding Information:
This work is dedicated to the memory of R.M. Steinman. The authors thank J. Adams for help with the figures and E. Shrestha for PCR genotyping Ldlr and Flt3-deficient mice. We also appreciate J. Breslow and J. Rodriguez for their valuable comments and technical help. We thank the Consortium for Functional Glycomics supported by NIGMS (GM62116) for DC-SIGN/Cd209a −/− mice. This work is supported by grants from National Institutes of Health (AI13013 and AI051573) (R.M.S), Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, South Korea (2011-0013669) (J.-H C), the Research Program for the National Research Laboratory (R0A-2007-000-20016-0), and a National Core Research Center grant (R15-2006-020) from the Ministry of Education, Science & Technology, South Korea (G.T.O.), and New York Community Trust's Francis Florio funds for blood diseases and the Rockefeller University clinical and translation science award pilot project from NIH/NCRR (5UL1RR024143-05) (C.C.).