Response by Mueller et al to Letter Regarding Article, "Deletion of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Accelerates Atherosclerosis Regression and Increases C-C Chemokine Receptor Type 7 (CCR7) Expression in Plaque Macrophages".

April 16, 2019 1983 Paul A. Mueller, PhD Lin Zhu, PhD Hagai Tavori, PhD Katherine T. Huynh, BS Ilaria Giunzioni, PhD John M. Stafford, MD, PhD MacRae F. Linton, MD Sergio Fazio, MD, PhD In Response: We thank Dr. Hoekstra and colleagues and Dr. Abbate and colleagues for the enthusiasm about our recent report of accelerated atherosclerosis regression attributable to the loss of macrophage low density lipoprotein receptor related protein 1 (LRP1) in mice.1 Dr. Hoekstra and colleagues posit that the use of apolipoprotein E-/recipient mice euthanized 2 weeks after bone marrow transplant may not be an appropriate control as additional plaque growth occurs in this group relative to wild-type or LRP1-/marrow recipients, whose cholesterol level decreases because of the return of apoE in plasma. They suggest that our results prove reduced progression, not increased regression of atherosclerosis. Previously published data from their group and others,2,3 as well as data in our manuscript, do not support this claim. It has long been established that apoE-/mice on a high-fat diet have similar cholesterol levels 2 weeks after bone marrow transplant irrespective of whether they receive wild-type (apoE+/+) or apoE-/bone marrow. Significant reductions in cholesterol levels start 4 weeks after transplant, when marrow recovery is complete and the full amount of macrophage-derived apoE is in circulation.4 Similar results were seen when the mice were on chow diet.5 Thus, any plaque growth that occurred between the bone marrow transplant and our baseline (2 weeks later) would have been similar between all groups. In addition, while they refer only to changes in plaque size, our data cover a comprehensive array of changes compatible with atherosclerosis regression, including fewer plaque macrophages, increased M2:M1 ratio, and increased macrophage emigration. Dr. Abbate and colleagues also bring up an excellent point regarding the role of LRP1 in macrophage biology. LRP1 is a multifunctional receptor that binds over 40 ligands, many with a role in survival and inflammatory processes.6 Our study deals with the complete absence of LRP1 in plaque macrophages, and thus, with the complete absence of any ligand-specific signaling through this receptor. They correctly note that apoE is one of these ligands, and question how the loss of macrophage LRP1 would change plaque regression in a model where apoE signaling is intact. To this point, we believe it is important to keep in mind that the loss of LRP1 accelerates progression of disease independently of apoE signaling.7