David Jackson

Having pioneered fundamental molecular research into the lymphatic system in Oxford, my particular interest has been in the biology of this critical but overlooked 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. Importantly, the filtering of lymph through intervening lymph nodes also allows the immune system to constantly monitor the periphery for microbial antigens as well as the metabolites and macromolecular degradation products known as DAMPs (Damage Associated Molecular Patterns) - "danger signals" that trigger inflammation and innate immune responses. Lymphatic vessels act as conduits not only for soluble antigens, but also for dendritic cells, monocytes, neutrophils and other immune cells that transport phagocytosed antigens to the lymph nodes to initiate and shape immune responses. The lymphatics are also 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. In addition, inborn and acquired defects in lymphatic vessel structure and function underly the hugely debilitating condition of lymphoedema, for which there is currently no effective treatment. 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 host anti-tumour immunity and from where they 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 immune cells, 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.

Recently, we determined the crystal structure and mechanics of LYVE-1, an undertaking that has revealed how this endothelial receptor binds and detaches from hyaluronan chains within the surface glycocalyx of dendritic cells and macrophages through an unusual sliding interaction that enables 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 lung disease, how they interface with the tumour cell hyaluronan glycocalyx to enable lymphatic metastasis and whether they may be manipulated to avoid transplant rejection. Our studies have also focussed on the key lymphatic derived chemokine CCL21, and the molecular mechanisms by which immune cells trigger its local on-demand secretion from lymphatic endothelium, to effect entry and trafficking within initial lymphatic capillaries.