Research Project
10270894
ABSTRACT Neutrophils constitute the first line of cellular defense against pathogenic microorganisms. In response to pro- inflammatory cues, unrestricted neutrophil activation induces tissue damage. To avoid deleterious effects to the host, neutrophil numbers, activation, and lifespan must be tightly regulated, but the molecular mechanisms that control neutrophils in the context of inflammatory disease remain elusive. Cardiovascular disease is the leading global cause of death. Recent evidence supports an important role for neutrophils in the development of coronary artery disease (CAD). Neutrophils are present in early aortic lesions and in rupture-prone atherosclerotic plaques, and a positive correlation between plasma levels of neutrophil secretory proteins and CAD has been established, suggesting that neutrophil exocytosis mediates detrimental effects in CAD. Furthermore, neutrophil production is increased in the bone marrow in atherosclerotic models and newly identified neutrophil precursors are now known to mediate inflammation. How neutrophil subsets contribute to disease progression in CAD has not been studied and the regulation of neutrophil diversity in disease is unknown. The inflammasome is an emerging driver in atherosclerosis; however, the role of the NLRP3 inflammasome activation selectively in neutrophils on atherogenesis has not been studied and the mechanisms regulating the functions of neutrophil lineage cells in the context of inflammasome activation and atherogenesis remain unknown. In this synergistic program, Project 1 Neutrophil Development During Inflammation and Atherosclerosis will study how neutrophil heterogeneity is modulated in human subjects with CAD, and how the NLRP3 inflammasome in neutrophil progenitors influences granulopoiesis and neutrophil heterogeneity in atherosclerosis. Project 2 Neutrophil Mechanisms During Inflammation and Atherosclerosis will test the hypothesis that hyperlipidemia differentially regulates vesicular trafficking and associated functions of neutrophil precursors in CAD, establish mechanisms of NLRP3-induced neutrophil exocytosis dysregulation and implement translational approaches to decrease neutrophil inflammation in CAD. Project 3 Neutrophil Survival and Demise During Inflammatory States will characterize the expression and function of components of the NLRP3 inflammasome in cells of the neutrophil lineage, and will define the effects of hyperlipidemia-induced inflammation and the roles of death receptor signaling in IL-1? production, mitochondrial apoptosis in viability of neutrophil lineage cells, and necroptosis signaling in atherogenesis. Our synergistic and unique program uses the complementary expertise of three renown researchers, experts in the areas of neutrophil development, neutrophil intracellular function regulation and inflammation, to study the central hypothesis that unrestricted activation of neutrophil progenitors and mature neutrophils is a fundamental process in cardiovascular disease. These studies will lead to novel approaches to treat neutrophil-mediated inflammation in CAD.
