Neutrophil Decision Making in Confined Environments in Health and Disease

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DESCRIPTION (provided by applicant): Neutrophil perfect functioning is essential for our well-being. Without neutrophils, we could only survive a few days the constant assault of bacteria and fungi in our normal environment. A tremendous selective pressure on neutrophils to function perfectly in a large number of conditions made neutrophils one of the most efficient and remarkable cells in terms of migration speed and ability to reach distant targets. However, there are several conditions where neutrophil activity could produce more damage than benefits. While neutrophil activation is protective after minor trauma, hyper-active neutrophils after major injuries have systemic deleterious effects and can effectively damage several organs and tissues, even in the absence of infection. Many conditions like chronic inflammatory diseases, immune reactions post-organ transplantation, or severe forms of asthma can be exacerbated by active neutrophils. Other times, neutrophils become unresponsive, simultaneously with down-regulation of the immune system, leading to, or facilitating septic states. Despite tremendous advances in the understanding of signaling molecules and pathways acting inside neutrophils, our understanding of the changes in neutrophils during disease processes is limited, and consequently, or abilities to modulate the activity of neutrophils in health and disease, restricted to very few options. We believe that advances in understating of neutrophil activity could come not only from molecular biology studies, but also from the development of new tools that would enable the discovery of neutrophil behavior in conditions relevant to in vivo situations. Recently, we demonstrated the surprisingly uniform motility of neutrophils when moving in micro-channels smaller in size than the cell. Using simple networks of channels, we have observed the surprising ability of neutrophils to find the shortest path towards a source of chemoattractant. We will further develop these complex devices to answer questions about the mechanical and chemical requirements for neutrophil decision making inside tissues, in health and disease, regarding the interplay between these in neutrophil biology, and to uncover new therapeutic strategies for controlling inflammation in burn and other critically ill patients. PUBLIC HEALTH RELEVANCE: Neutrophil perfect functioning is essential for our well-being and protection against many infectious agents from our close environment. . However, there are several conditions where neutrophil activity could produce more damage than benefits and new tools are needed to better characterize neutrophils in these conditions. While current methods for studying neutrophils relay exclusively on chemical stimulation of the cells, we have recently shown that the mechanical confinement of the neutrophils in small channels is of utmost importance for neutrophil behavior. To better understand neutrophil alterations of activity following burn injuries, we will apply new microfluidic tools and quantify the responses of neutrophils to combined mechanical and chemical stimuli, in health and disease conditions. This understanding could results in new opportunities for uncovering effective therapeutic strategies for controlling inflammation in burn and other critically ill patients.