Chemokine gradient development around lymphatic vessels during immune and inflammatory responses.

The precisely orchestrated migration of leukocytes is a key feature of all immune and inflammatory responses, including those that occur in infectious diseases. Rapid leukocyte transport around the body is facilitated by fluid delivery in the blood and lymphatic vessels. However, their guidance to key destinations in tissues, lymph nodes or other tissue spaces is driven by a family of small secreted proteins called chemokines. Despite major advances in understanding chemokine function, it is still unclear how chemokine gradients are formed, maintained and regulated in tissues. Chemokines are known to bind to extra-cellular matrix (ECM) components and this adhesion is likely to play a key role. Interstitial fluid flow will also contribute to chemokine gradient formation, and in the case of chemokine production near blood or lymphatic vessels, the transmural movement of fluid is likely to advect chemokines further into tissues than would be possible by pure diffusion. ‘Atypical’ chemokine receptors (ACKRs), a small family of molecules that scavenge and destroy extracellular chemokines are also likely to play a critical role in establishing, stabilizing and regulating chemokine gradients. The type of leukocyte migration induced depends on chemokine context, with soluble chemokine gradients directing chemotactic cell movement (migration up concentration gradients), while immobilized chemokine gradients induce integrin-dependent haptotaxis (migration up adhesion gradients).
The mechanisms that set up these gradients include diffusion, advection (fluid movement), cell-mediated scavenging, and selective binding to extracellular matrix (ECM), some of which may be modified during inflammation. The aim of this project will therefore be to develop mathematical models of chemokine gradient development during an immune or inflammatory response. The models will be developed in collaboration with immunologists based at the University of Glasgow (Profs Nibbs and Graham) [1], and a bioengineer at Imperial College London (Prof James Moore) who will be quantifying chemokine transport dynamics using a novel microfluidic platform to obtain a better understanding of chemokine transport and distribution in interstitial tissues around lymphatic vessels.