Regulation of macrophage polarization in atherosclerosis regression

New York University School Of Medicine, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Coronary artery disease (CAD), the direct result of atherosclerosis, is the most common cause of death in the USA and other western countries. Since coronary plaques begin their progression in childhood, their reversal is an important clinical goal in adulthood. This reversal is, at best, partial with current therapies, making the need to understand the mechanisms behind plaque progression and regression an important goal for the development of more effective therapeutics for CAD. Atherosclerosis progression represents a failure to resolve inflammation with the central inflammatory cell in the plaque being the macrophage. Macrophages (MØs) can differentiate from infiltrating monocytes of hematopoietic origin during inflammatory responses or be derived from resident progenitors that are already seeded in the tissues during embryonic development. Type 1 cytokines (e.g. Interferon gamma) and Toll-like Receptor agonists classically polarize, or activate, MØs to the M1 state, whereas the Type 2 cytokines Interleukin-4 (IL-4) and IL-13 will polarize, or alternatively activate, MØs to the M2 state. While the majority of MØs in mouse and human plaques have the M1 phenotype, plaque regression in a variety of mouse models, as first demonstrated by Dr. Edward A. Fisher's lab, is characterized by the enrichment of MØs that are in the alternatively activated M2 state and also by the resolution of inflammation. Preliminary data from our lab have found that regression is impaired in Ccr2-/-, Cx3cr1-/-, or Stat6-/- mice, indicating that infiltrating monocytes that become M2 MØs in plaques are derived from circulating Ly6C hi monocytes, which receive signals through IL-4 and/or IL-13 signaling to become M2 MØs. Furthermore, the M2 polarization appears to be required for regression, likely reflecting their ability to resolve inflammation. Our proposal aims to definitively show the origin of M2 MØs (circulating vs. resident, Ly6C hi vs low) and further understand the regulatory signals that induce M2 MØ polarization during plaque regression.