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)
Type
Research Project (R01)
Project #
2R01HL095612-06
Application #
8693287
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Olive, Michelle
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Swirski, Filip K (2014) Monocyte recruitment and macrophage proliferation in atherosclerosis. Kardiol Pol 72:311-4
Kobzik, Lester; Swirski, Filip K (2014) MARCOing monocytes for elimination. Sci Transl Med 6:219fs4
Hilgendorf, Ingo; Theurl, Igor; Gerhardt, Louisa M S et al. (2014) Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity. Circulation 129:1677-87
Hilgendorf, Ingo; Gerhardt, Louisa M S; Tan, Timothy C et al. (2014) Ly-6Chigh monocytes depend on Nr4a1 to balance both inflammatory and reparative phases in the infarcted myocardium. Circ Res 114:1611-22
Nahrendorf, Matthias; Swirski, Filip K (2014) Fluorescent leukocytes enter plaque on the microscope stage. Circ Res 114:740-1
Swirski, Filip K; Nahrendorf, Matthias (2014) Do vascular smooth muscle cells differentiate to macrophages in atherosclerotic lesions? Circ Res 115:605-6
Swirski, Filip K; Hilgendorf, Ingo; Robbins, Clinton S (2014) From proliferation to proliferation: monocyte lineage comes full circle. Semin Immunopathol 36:137-48
Weber, Georg F; Chousterman, Benjamin G; Hilgendorf, Ingo et al. (2014) Pleural innate response activator B cells protect against pneumonia via a GM-CSF-IgM axis. J Exp Med 211:1243-56
Nahrendorf, Matthias; Swirski, Filip K (2014) Regulating repair: regulatory T cells in myocardial infarction. Circ Res 115:7-9
Pittet, Mikael J; Nahrendorf, Matthias; Swirski, Filip K (2014) The journey from stem cell to macrophage. Ann N Y Acad Sci 1319:1-18

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