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 (Ms) 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, Ms to the M1 state, whereas the Type 2 cytokines Interleukin-4 (IL-4) and IL-13 will polarize, or alternatively activate, Ms to the M2 state. While the majority of Ms 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 Ms 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 Ms in plaques are derived from circulating Ly6C hi monocytes, which receive signals through IL-4 and/or IL-13 signaling to become M2 Ms. 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 Ms (circulating vs. resident, Ly6C hi vs low) and further understand the regulatory signals that induce M2 M polarization during plaque regression.
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 because they do not adequately address the failure to resolve the macrophage- mediated inflammation that is characteristic of plaque progression. Our proposal aims to understand the origin and polarization regulation of M2 macrophages, which are involved in resolving inflammation in regressing atherosclerotic lesions, with the hope that these insights will lead to more effective therapies against CAD.
|Rahman, Karishma; Fisher, Edward A (2018) Insights From Pre-Clinical and Clinical Studies on the Role of Innate Inflammation in Atherosclerosis Regression. Front Cardiovasc Med 5:32|
|Rahman, Karishma; Vengrenyuk, Yuliya; Ramsey, Stephen A et al. (2017) Inflammatory Ly6Chi monocytes and their conversion to M2 macrophages drive atherosclerosis regression. J Clin Invest 127:2904-2915|