Professor of Human Immunology
Molecular mechanisms of lymphatic trafficking in health and disease
Having pioneered molecular research into the lymphatic system in Oxford, my group is particularly focussed on the biology of this critical vasculature in the context of inflammation, immunity and cancer. The elaborate network of lymphatic vessels collects fluids leaked into tissues from the blood vessels, and returns it as lymph to the venous circulation. More importantly, the filtering of lymph through intervening lymph nodes allows the immune system to constantly monitor the periphery for microbial antigens, and for the metabolites and macromolecular degradation products known as PAMPs (pathogen associated molecular patterns) danger signals and DAMPs (damage associated molecular patterns) that trigger innate and then adaptive immune responses. The lymphatic vessels act as conduits not only for soluble antigens, but also for dendritic cells, monocytes, neutrophils and other leukocytes that transport phagocytosed antigens to the lymph nodes to initiate and shape immune responses. The lymphatics are important for clearance of immune cells from tissues including the heart, lung and intestine during the resolution of inflammation, the transport of dietary lipids from the intestines and the drainage of CSF in the brain and CNS. Finally, lymphatic vessels are also a key pipeline for the dissemination of tumour cells to draining lymph nodes where they manipulate immune receptor expression to suppress the host immune response and from which hey can invade HEVs to effect systemic metastasis. The recognition that lymphatics and lymphangiogenesis play such important roles in these critical processes in both health and disease has brought the field to the forefront of immunology and cell biology, and now is an exciting time to be involved in such research.
Our focus is on the mechanisms by which leukocytes, tumour cells and certain bacterial pathogens enter the lymphatic vessels from the surrounding tissues, the adhesion molecules and chemokines they engage, and the transmigratory mechanisms involved. We are also interested in the fate of leukocytes, particularly neutrophils, arriving at draining lymph nodes via the lymph route, and the consequences of their arrival for altering the quality of the immune response.
An integral part of our work focusses on the extracellular matrix glycosaminoglycan hyaluronan and its endothelial receptors CD44 and LYVE-1 (LYmphatic Vessel Endothelial receptor 1), the latter of which was first cloned and identified in my laboratory and is now recognised as a key regulator of endothelial junctional permeability and leukocyte transmigration. Using Lyve1-/- mice and a panel of fluorescently tagged transgenic mice in models of inflammation and cancer, combined with confocal and super-resolution imaging and in vitro cell biology techniques, we are studying the involvement of this key receptor and its ligand hyaluronan in leukocyte trafficking, microbe dissemination and tumour metastasis. Our aim is to understand these key biological processes, and ultimately to manipulate them for therapeutic advantage. In doing so, my group applies a variety of techniques from microscopy to molecular biology , biophysical analyses and X-Ray crystallography through multiple collaborations with leading scientists both in Oxford, the UK and internationally. Currently, we are involved in determining the crystal structure and mechanics of LYVE-1 in order to understand how it binds and detaches from the hyaluronan surface glycocalyx of dendritic cells and macrophages to enable their entry to lymphatic vessels. In addition, we are helping to research how the lymphatics contribute to cardiac repair and re-modelling after mycocardial infarction, how they contribute to inflammatory bowel disease, how they interface with the tumour cell hyaluronan glycocalyx to enable lymphatic metastasis and how they may be manipulated to avoid transplant rejection. Our studies also focus on the key lymphatic derived chemokine CCL21, and unravelling the mechanisms by which immune cells trigger its local on-demand secretion from lymphatic endothelium to effect entry and trafficking within initial lymphatic capillaries.