Professor of Human Immunology
My group is interested in the lymphatic system. This elaborate network of 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 also a pipeline for metastasizing tumour cells to spread to distant tissues, and to colonize lymph nodes where they can manipulate the immune response, and prevent their recognition by the immune system. The recognition that lymphatics play such an important role in each of these critical processes has brought the field to the forefront in immunology and cell biology, and now is an exciting time to be involved in the 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 hyaluronan receptor Lyve-1 (LYmphatic Vessel Endothelial receptor 1), which was originally cloned and identified in my laboratory and is emerging as a regulator of endothelial junctional permeability and leukocyte transmigration. Using Lyve-1-/- 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. My group applies a variety of techniques, and for example we are interested in determining the crystal structure of the ligand-binding domain in Lyve-1 in order to understand how interactions with hyaluronan during lymphatic trafficking are regulated by receptor homodimerization and clustering. Our studies also extend beyond hyaluronan receptors to include the roles of lymphatic derived chemokines such as CCL21, CX3CL (fractalikne) and IL-8 in leukocyte chemotaxis and molecules that influence endothelial junctional permeability.
The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction.
Vieira JM. et al, (2018), J Clin Invest
Hyaluronan Receptor LYVE-1-Expressing Macrophages Maintain Arterial Tone through Hyaluronan-Mediated Regulation of Smooth Muscle Cell Collagen.
Lim HY. et al, (2018), Immunity
Lymphatic exosomes promote dendritic cell migration along guidance cues.
Brown M. et al, (2018), J Cell Biol, 217, 2205 - 2221
Hyaluronan in the lymphatics: The key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking.
Jackson DG., (2018), Matrix Biol
TGFβ counteracts LYVE-1-mediated induction of lymphangiogenesis by small hyaluronan oligosaccharides.
Bauer J. et al, (2018), J Mol Med (Berl), 96, 199 - 209