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.
Extracellular bacterial lymphatic metastasis drives Streptococcus pyogenes systemic infection.
Siggins MK. et al, (2020), Nat Commun, 11
Hyaluronan derived from the limbus is a key Regulator of Corneal Lymphangiogenesis
Sun M. et al, (2020), INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 61
The cortical actin network regulates avidity-dependent binding of hyaluronan by the lymphatic vessel endothelial receptor LYVE-1.
Stanly TA. et al, (2020), J Biol Chem, 295, 5036 - 5050
Distinct requirements for tissue-resident myeloid lineages during cardiac lymphatic development
JACKSON D. et al, (2020), eLife, Submitted
TNF-derived peptides inhibit tumour growth and metastasis through cytolytic effects on tumour lymphatics.
Lu W. et al, (2019), Clin Exp Immunol