(313g) Spatial Mechanisms for the Stepwise Navigation of Neutrophils

In response to infection, immune cells are recruited to fight off invading microbes. Chemotaxis, the process by which cells move in response to chemical gradients, plays a prominent role in this defense mechanism. A number of chemical signals, called chemoattractants, are produced at or proximal to sites of infection and diffuse into the surrounding tissue. Immune cells sense these chemoattractants and move in the direction where their concentration is greatest, thereby locating the source of attractants and the associated targets. Leading the assault against new infections is a specialized class of white blood cells called neutrophils, which normally circulate in the blood stream. Upon activation, neutrophils adhere to and squeeze through the vascular endothelium, crawling to sites of infection and inflammation. There they phagocytose bacteria and release a number of proteases and reactive oxygen intermediates with antimicrobial activity.

Neutrophils respond to many different chemoattractants. One open question is how they locate their targets in complex environments consisting of many different chemoattractant species and sources. Successful navigation under such conditions necessitates a robust mechanism for interpreting and prioritizing the signals received. Recent studies have implicated an intrinsic signaling hierarchy among the known chemoattractants, resulting in their classification as either end target or endogenous species. In particular, the end target variants, produced exclusively at or near the site of infection, have been found to consistently take precedence over the endogenous species. Endogenous chemoattractants, on the other hand, induce an apparently counter-intuitive chemotactic response within the cells, where distant sources are favored over proximal sources regardless of their type.

To date, several attempts to explain this preferential bias toward distant sources have involved temporal mechanisms such as sensory adaptation or an inherent delay in the cell response. However, the possibility of spatial effects has remained unaddressed. Here, we present a mathematical model of neutrophil chemotaxis to show that the observed bias can also be recovered by a purely spatial mechanism - the movement of the cell through changing environments naturally leads to changes in sensitivity to different concentrations of the chemoattractants. Moreover, we show that this mechanism enhances the ability of neutrophils to locate target infections within complex environments. This corroborates a recent hypothesis that neutrophils may migrate in a stepwise fashion between chemokine sources as a means to approach distant end targets. Finally, we present experimental results to validate the predictions of our model.