Coronary artery disease (CAD), the direct result of atherosclerosis, is the most common cause of death in the USA and other western countries. Decreasing CAD risk by current therapies confers incomplete protection from myocardial infarctions. Since coronary plaques begin their progression in childhood, new directions are needed to reverse them. Our understanding of atherosclerosis regression, however, lags far behind what is known about plaque progression. This proposal represents the combined efforts of 3 laboratories with complementary expertise to expand conceptually and technically the efforts to address this imbalance that the previous funding cycles have supported. There is increasing recognition that plaque progression represents a failure to resolve inflammation. The central inflammatory cell in the plaque is the macrophage. Macrophages can differentiate from infiltrating monocytes of hematopoietic origin during inflammatory responses or are derived from resident progenitors that are already seeded in the tissues during embryonic development. Type 1 cytokines (e.g., IFNg) and TLR agonists classically activate macrophages (referred to as M1 macrophages), whereas the Type 2 cytokines IL- 4 and IL-13 will alternatively activate macrophages (referred to as M2 macrophages). While the majority of macrophages in mouse and human plaques have the M1 phenotype, we have found that plaque regression in a variety of mouse models we have introduced is characterized by the enrichment of macrophages that are in the alternatively activated M2 state. Furthermore, exciting preliminary data strongly suggest that this enrichment is required for regression and that IL-4 is the key cytokine regulating this enrichment. The major objective, then, of this proposal is to more deeply understand the source, regulation, and function of M2 macrophages in plaque regression. We propose to:
Aim 1 : Test the hypothesis that M2 macrophages in regressing plaques are derived from newly recruited infiltrating Ly6C high monocytes.
Aim 2 : Determine the cellular source of IL-4 responsible for polarizing M2 macrophages in regressing plaques.
Aim 3 : Test the hypothesis that M2 macrophages in regressing plaques are regulating inflammatory responses by promoting the differentiation of Foxp3+ regulatory T cells, which are known to be anti- inflammatory and atheroprotective in progressing plaques.

Public Health Relevance

Current treatments of coronary artery disease, the direct result of atherosclerosis, still leave many patients at significant risk of heart attacks and stroks. Using novel mouse models, we have shown that the high inflammatory state of disease-causing cells in atherosclerosis, macrophages, is not permanent as previously thought, and our major goal is to learn the mechanisms by which these cells can be made to be anti- inflammatory and regress the plaques. The results should point to key pathways and targets to augment current therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084312-11
Application #
9438408
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Liu, Lijuan
Project Start
2006-04-01
Project End
2020-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
11
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10010
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