Mammalian white blood cells are known to bias the direction of their movement along concentration gradients of specific chemical stimuli, a phenomenon called chemotaxis. Chemotaxis of leukocyte cells is central to the acute inflammatory response in living organisms and other critical physiological functions. On a molecular level, these cells sense the stimuli termed chemotactic factor (CF) through specific cell surface receptors that bind CF molecules. This triggers a complex signal transduction process involving intracellular biochemical pathways and biophysical events, eventually leading to the observable chemotactic response. Several investigators have shown theoretically that statistical fluctuations in receptor binding lead to "noisy" intracellular signals, which may explain the observed imperfect chemotactic response to a CF gradient. The most recent dynamic model (Tranquillo and Lauffenburger, J. Math. Biol.25, 229-262. 1987) couples a scheme for intracellular signal transduction and cell motility response with fluctuations in receptor binding. However, this model employs several assumptions regarding receptor dynamics that are now known to be oversimplifications. We extend the earlier model by accounting for several known and speculated chemotactic receptor dynamics, namely, transient G-protein signaling, cytoskeletal association, and receptor internalization and recycling, including statistical fluctuations in the numbers of receptors among the various states. Published studies are used to estimate associated constants and ensure the predicted receptor distribution is accurate. Model analysis indicates that directional persistence in uniform CF concentrations is enhanced by increasing rate constants for receptor cytoskeletal inactivation, ternary complex dissociation, and binary complex dissociation, and by decreasing rate constants for receptor internalization and recycling. For most rate constants, we have detected an optimal range that maximizes orientation bias in CF gradients. We have also examined different desensitization and receptor recycling mechanisms that yield experimentally documented orientation behavior. These yield novel insights into the relationship between receptor dynamics and leukocyte chemosensory movement behavior.
Bibliographical noteFunding Information:
Support from an NSF Research Initiation Award NSF/EET-8809439 and an NSF Presidential Young Investigator Award NSF/BCS-8957736 and a grant from the Minnesota Supercomputer Institute to RTT are gratefully acknowledged.