PROJECT SUMMARY/ABSTRACT
Vascular inflammation is a key component of atherosclerosis that contributes to plaque instability and clinical
cardiovascular events, including ischemic stroke, and myocardial infarction (MI). Despite decades of research,
the immune mechanisms contributing to these processes remain largely unresolved. Among myeloid cells,
monocytes/macrophages are believed to be major players in the pathogenesis of cardiovascular diseases
(CVD). Emerging single-cell technologies have unveiled that the macrophage pool in CVD is vastly
heterogeneous, containing a plethora of transcriptionally distinct subpopulations. In chronic inflammatory
diseases, GATA3 is regarded as a master regulator of the phenotype of T-cells and other immune cells.
However, the role of GATA3 in the regulation of the phenotype of macrophages is completely unknown. For
the first time, we demonstrated that GATA3 was expressed in macrophages and GATA3+ macrophages
accumulated into the myocardium after acute MI and adversely affected the cardiac function. In fact, the
deficiency of GATA3+ macrophages led to a significant improvement of cardiac function after acute MI. Cell
culture studies revealed that IL-33 stimulated the expression of GATA3 in macrophages. Our long term goal is
to dissect the mechanism/s that regulates the phenotype and function of GATA3+ macrophages in CVD. Our
rationale is that by identifying the mechanism/s that control the phenotype of GATA3+ macrophages in the
setting of CVD will offer new therapeutic opportunities. In Specific Aim 1, we will utilize novel mouse models in
combination with transplant immunology to test the hypothesis that macrophage-specific IL-33R signaling
controls the recruitment and function of GATA3+ macrophages in CVD. Most studies aimed at characterizing
the phenotypes of human macrophages are performed in vitro; however, the relevance to the function of
macrophages in vivo is uncertain. The role of GATA3 signaling in the activity of human macrophages in vitro
and in vivo is completely unknown. We have generated macrophage-specific humanized GATA3 sufficient
mice as a novel preclinical platform to test the hypothesis that human GATA3 signaling controls the
phenotype/function of macrophages after acute MI in Specific Aim 2. In depth knowledge of atherosclerotic
plaques is a prerequisite to preventing and treating MI. We found that GATA3+ macrophages accumulated into
atherosclerotic plaques, and GATA3 expression in macrophages is stimulated by cholesterol crystals.
However, the function of GATA3+ macrophages in atherosclerosis is completely unknown. In Specific Aim 3,
we will use atheroma-prone mouse models in combination with bone marrow transplantation to test the
hypothesis that GATA3+ macrophage subset/s are atherogenic. The proposed research is innovative because
we will investigate the effect of GATA3+ macrophages in CVD, a heretofore-unexamined process.