Macrophages inhabit all major organs. These large phagocytic myeloid leukocytes' primary purpose may be to maintain tissue integrity by ingesting and eliminating dangerous or dispensable material. From clearing bacteria to pruning neurons, macrophages adapt their functions to meet the needs of their home tissues. The recent recognition that tissue macrophages derive from different sources, coupled with the idea that environmental cues and inflammatory stimuli can sculpt and agitate homeostatic order, provides a frame of reference from which we can decipher the breadth and depth of macrophage activity. Here, I will use: (i) models of atherosclerosis (Ldlr?/?, Apoe?/?, PCSK9-Ad) and myocardial infarction (permanent ligation, ischemia reperfusion); (ii) environmental stimuli (diet, sleep fragmentation); (iii) transgenic and knockout mice (Cx3cr1CreERT2 R26-tdT, IL-3?/?, Csf2?/?, Csf2rb?/?, CD123?/?); (iv) surgical procedures (parabiosis, spleen transplantation); (v) real-time imaging technologies (PET-MRI, intravital microscopy); and (vi) many immunology and molecular biology techniques to investigate macrophage development and function in cardiovascular disease. In aggregate, these tools will allow to decipher how macrophages of different orgins (yolk sac, fetal liver, adult bone marrow, adult spleen, vascular smooth muscle cells) and in different locations (adventitia, intima, ischemic myocardium, remote myocardium) collaborate with and differ from one another during atherosclerosis and its complications. A central concept of this grant is the tension between macrophage ontogeny as a determinant of macrophage function and the idea that tissues condition macrophage activities and supplant the influence of macrophage ontogeny in favor of environmental demands.

Public Health Relevance

Macrophages are among the most important cells that contribute to, and protect against, atherosclerosis and its complications. We still have major gaps in our understanding of how macrophage function is controlled. Building on a nature vs. nurture scaffold, I will explore and elucidate how development and environment shape macrophage function in atherosclerosis and myocardial infarction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Unknown (R35)
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Special Emphasis Panel (ZHL1)
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Olive, Michelle
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Massachusetts General Hospital
United States
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Fayad, Zahi A; Swirski, Filip K; Calcagno, Claudia et al. (2018) Monocyte and Macrophage Dynamics in the Cardiovascular System: JACC Macrophage in CVD Series (Part 3). J Am Coll Cardiol 72:2198-2212
Nairz, Manfred; Haschka, David; Dichtl, Stefanie et al. (2017) Cibinetide dampens innate immune cell functions thus ameliorating the course of experimental colitis. Sci Rep 7:13012
Keliher, Edmund J; Ye, Yu-Xiang; Wojtkiewicz, Gregory R et al. (2017) Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease. Nat Commun 8:14064
Franck, Grégory; Mawson, Thomas; Sausen, Grasiele et al. (2017) Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice: Implications for Superficial Erosion. Circ Res 121:31-42
Canali, Susanna; Zumbrennen-Bullough, Kimberly B; Core, Amanda B et al. (2017) Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice. Blood 129:405-414
Anzai, Atsushi; Choi, Jennifer L; He, Shun et al. (2017) The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes. J Exp Med 214:3293-3310
Hulsmans, Maarten; Clauss, Sebastian; Xiao, Ling et al. (2017) Macrophages Facilitate Electrical Conduction in the Heart. Cell 169:510-522.e20