Atherosclerosis is a lipid-driven inflammatory disease characterized by the accumulation of lipoproteins and leukocytes in the vessel wall. Among the leukocytes, macrophages are the most numerous and contribute to the development and exacerbation of atherosclerosis decisively. Lesional macrophages derive from circulating monocytes. In the mouse, bone marrow and spleen-derived Ly-6Chigh monocytes accumulate in lesions continuously, and preferentially over the course of disease. Our recent work has shown that, in addition to monocyte influx, mature macrophages proliferate in situ. Although lesional macrophages ultimately derive from circulating monocytes, macrophage proliferation is a dominant mechanism of macrophage accumulation in established atherosclerosis. The molecular mechanisms that orchestrate monocyte influx and macrophage proliferation differ. On the one hand, production and influx of monocytes depends on growth factors and chemokines. On the other hand, local macrophage proliferation depends in part on signaling via the scavenger receptor SR-A. In the grant, we hypothesize that the relative contribution of monocyte influx and macrophage proliferation is fundamental to the development and exacerbation of atherosclerosis. We propose to profile the relative importance of recruitment and proliferation, elucidate and target the molecular mechanisms that drive these processes, and correlate macrophage proliferation with the composition of human lesions. The study is clinically relevant because targeting specific inflammatory processes in atherosclerosis is a major clinical goal. It is therefore essential to know whether and when monocyte recruitment, macrophage proliferation, or both, need to be targeted.

Public Health Relevance

Atherosclerosis is a lipid-driven inflammatory disease of lipoprotein and leukocyte accumulation. Monocytes and macrophages are essential to the development and exacerbation of disease, and are therefore possible therapeutic targets. Development of atherosclerosis involves the recruitment of monocytes to the vessel wall. Recent data also show that lesional macrophage proliferation is an important mechanisms that drives the accumulation of macrophages in established disease. Is one process more important and dangerous than the other? In this grant, we will evaluate the relative importance of monocyte influx and macrophage proliferation to the development of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095612-08
Application #
9038415
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Olive, Michelle
Project Start
2009-05-01
Project End
2018-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
8
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
McAlpine, Cameron S; Swirski, Filip K (2016) Circadian Influence on Metabolism and Inflammation in Atherosclerosis. Circ Res 119:131-41
Swirski, Filip K; Robbins, Clinton S; Nahrendorf, Matthias (2016) Development and Function of Arterial and Cardiac Macrophages. Trends Immunol 37:32-40
Nahrendorf, Matthias; Swirski, Filip K (2016) Innate immune cells in ischaemic heart disease: does myocardial infarction beget myocardial infarction? Eur Heart J 37:868-72
Libby, Peter; Nahrendorf, Matthias; Swirski, Filip K (2016) Leukocytes Link Local and Systemic Inflammation in Ischemic Cardiovascular Disease: An Expanded ""Cardiovascular Continuum"". J Am Coll Cardiol 67:1091-103
Lindau, Alexandra; Härdtner, Carmen; Hergeth, Sonja P et al. (2016) Atheroprotection through SYK inhibition fails in established disease when local macrophage proliferation dominates lesion progression. Basic Res Cardiol 111:20
Sager, Hendrik B; Hulsmans, Maarten; Lavine, Kory J et al. (2016) Proliferation and Recruitment Contribute to Myocardial Macrophage Expansion in Chronic Heart Failure. Circ Res 119:853-64
Dutta, Partha; Hoyer, Friedrich Felix; Sun, Yuan et al. (2016) E-Selectin Inhibition Mitigates Splenic HSC Activation and Myelopoiesis in Hypercholesterolemic Mice With Myocardial Infarction. Arterioscler Thromb Vasc Biol 36:1802-8
Tang, Jun; Baxter, Samantha; Menon, Arjun et al. (2016) Immune cell screening of a nanoparticle library improves atherosclerosis therapy. Proc Natl Acad Sci U S A 113:E6731-E6740
Sager, Hendrik B; Dutta, Partha; Dahlman, James E et al. (2016) RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction. Sci Transl Med 8:342ra80
Theurl, Igor; Hilgendorf, Ingo; Nairz, Manfred et al. (2016) On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver. Nat Med 22:945-51

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