Investigating the regulation of chemoattractant prioritization in human neutrophils

University Of California At Davis, Davis CA

Investigators

Linked publications, trials & patents

Abstract

Project Summary. Neutrophils are the most abundant white blood cell, comprising 50-60% of circulating leukocytes. In response to injury or infection, neutrophils migrate from the vasculature to affected tissues. This migration requires dynamic prioritization of responses to multiple chemoattractants, which compete with one another to successfully guide neutrophils through microenvironmental barriers and new signaling environments (e.g. injured target tissue). Once they reach target tissues, neutrophils act as first responders, clearing debris, releasing cytotoxic granules and recruiting other immune cells to follow. This orchestral role makes neutrophils an indispensable part of the early immune response. However, inappropriate or excessive neutrophil recruitment is implicated in a variety of life-threatening autoimmune and inflammatory diseases. For example, neutrophil recruitment to sites of atherosclerotic lesions is implicated in destabilization of these lesions and increased risk of cardiac infarction and stroke. Thus, better understanding neutrophil recruitment is critical, particularly in the context of sterile injury. Chemoattractant prioritization is central to neutrophil recruitment. Yet, the mechanism enabling prioritization is unclear. Several theories have been proposed to explain prioritization including the activation of distinct signaling pathways by chemoattractant receptors. However, my preliminary data suggest a novel hypothesis: differences in the temporal dynamics of shared signaling pathways. Here, I focus on the prioritization of bacteria-derived formyl-peptides over host-derived Leukotriene B4. The proposed work aims to uncover the mechanism of prioritization by investigating how chemoattractant receptors confer priority and characterizing the kinetic and temporal dynamics of key signaling pathways. Finally, to gain a clearer understanding of how chemoattractant prioritization is regulated at the receptor level, attractant- specific signaling dynamics will be related to specific receptor sequences. This work has the potential to uncover novel therapeutic targets for tuning neutrophil recruitment, thereby reducing the inflammatory response and associated collateral tissue damage.