Neutrophil Survival and Demise During Inflammatory States

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Abstract Interleukin-1b is a pro-inflammatory cytokine in cardiovascular disease (CVD) contributing to life-threatening cardiovascular events including myocardial infarction and stroke. Interleukin-1a also contributes to disease. The cell types and signaling pathways that control IL-1a/b production remains to be comprehensively evaluated. This study will investigate the neutrophil lineage in cardiovascular disease and their role in IL-1a/b production. Neutrophil accumulation in tissues is a hallmark feature of many acute and chronic inflammatory diseases, including coronary artery disease. Despite our broad understanding of the factors controlling neutrophil production and function, we lack a comprehensive understanding of cell death signaling in the neutrophil lineage at steady state and during inflammation. In patients with coronary artery disease, neutrophils accumulate in atherosclerotic plaques, and are enriched in areas that are prone to rupture and intraplaque hemorrhage. In mouse models of coronary artery disease (CAD), atherosclerotic plaques feature an accumulation of neutrophils in early and advanced stages of disease, and neutrophil depletion impairs the early recruitment of monocytes to the aortic arch and the progression of atherosclerosis. We hypothesize that neutrophils release IL-1 in CAD by engaging the NLRP3 inflammasome, the Caspase-8-regulated apoptosis pathway, or the MLKL-regulated necroptotic pathway. The control of Caspase-8-dependent apoptosis and IL-1 release by Bcl-2 family members will be evaluated in neutrophil lineage cells including neutrophil progenitors (NePs), immature neutrophils, and mature neutrophils. The effects of CAD on IL-1 production and cell death signaling in human neutrophil lineage cells will be assessed. This research will identify pro-survival signals in coronary artery disease increasing neutrophil longevity, and pro-death signals that control IL-1 production, formation of neutrophil extracellular traps, release of mitochondria, and inflammatory forms of cell death.