Neutrophil Mechanisms During Inflammation and Atherosclerosis

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Project Summary/Abstract Intracellular vesicular transport is essential for all aspects of neutrophil physiology and defects in this mechanism leads to disease in humans. Uncontrolled neutrophil activation and neutrophil secretory proteins are associated with the development of systemic inflammation, endothelial dysfunction, coronary artery disease (CAD) and autoinflammatory disease. We found that the recently identified neutrophil progenitors (NePs) and immature neutrophils contain morphologically and functionally unique secretory organelles. We also show that both the inflammasome and exposure to high-fat diets (HFD) differentially regulate neutrophil activation and this is affected by their maturation state. We have identified several key regulatory factors essential for the control of neutrophil granule trafficking in vitro and in vivo, including the small GTPase Rab27a, its effectors JFC1 and Munc13-4, and NeP-specific effectors. The control of specific vesicular trafficking pathways in neutrophil precursors constitutes a unique approach to reduce inflammatory disorders highlighting the need for treatments targeting these pathways. In this application, we will use genetically modified mouse models and human neutrophils, to test the hypothesis that molecular mechanisms of vesicular trafficking and neutrophil functions differentially modulate neutrophils- and NePs-mediated inflammation in CAD. We will study neutrophil functions in hyperlipidemia in CAD (collaboration with Project 1) and inflammasome-mediated mechanisms (collaboration with Project 3). We will use novel inhibitors of neutrophil secretion in translational approaches to reduce inflammation. The significance of the proposed research is that elucidating the mechanisms regulating vesicular trafficking and secretion in neutrophils and NePs will lead to effective strategies for the treatment of systemic inflammation in CAD. To test our hypotheses we propose the following Specific Aims: 1) Test the hypothesis that hyperlipidemia differentially regulates vesicular trafficking and associated functions in neutrophils and precursors in CAD; 2) Elucidate the mechanisms of azurophilic granule exocytosis dysregulation induced by inflammasome activation in mature neutrophils and their precursors; 3) Mechanistic and translational studies of neutrophil- mediated inflammation in CAD. The proposed research should uncover the molecular mechanisms regulating vesicular transport in neutrophil precursors and lead to effective new strategies to treat inflammation in CAD.