Louise Johnson

The lymphatic system is an extensive network that drains fluid, macromolecules and immune cells from peripheral tissue, filters through lymph nodes for immune surveillance, then drains to the blood circulation. However, the lymphatics are much more complex and fascinating than simply being the “sewer of the vasculature” and this vital component of the immune system is implicated in many different diseases throughout the body. In the heart, lymphatic trafficking of leukocytes following the acute inflammatory response after myocardial infarction is essential for tissue repair and recovery [1]. In the brain, meningeal lymphatics play critical roles in inflammatory and degenerative diseases such as multiple sclerosis, aging and Alzheimer’s disease [2] . In the gut, lymphatics are vital for lipid transport, with roles in maintaining villi architecture, obesity and metabolism [3]. Indeed, in all peripheral tissue, lymphatics are involved in immunity and inflammation, from the initial primary immune response to resolution and recovery.

The lymphatic system is unlike the blood vasculature in that it is not a closed circuit, but instead begins in peripheral tissue with blind-ended capillaries which have a distinctive architecture that equips them for uptake of fluids and cells [4] (Figure 1). Rather than the continuous junctions found in blood vessels, the initial lymphatics have discontinuous interrupted junctions “buttoned” together with molecules such as the adherens junction protein VE-cadherin, interspersed with scalloped edges (flaps) expressing the hyaluronan receptor LYVE-1 [4, 5], (Figure 2).

My research improves our understanding of the molecules involved in mediating the first key steps of immune cell egress from tissue, and entry into initial lymphatic capillaries. Regulation of this determines which leukocytes can enter, how an efficient primary immune response is instigated and which immune cells can be successfully cleared from tissue during resolution of inflammation. Previously, we were the first to demonstrate that the lymphatic endothelium plays an active role in mediating leukocyte trafficking in inflammation, by adopting an entirely new expression profile of adhesion molecules and chemokines [6-11]. More recently, we identified a key role for LYVE-1 in mediating docking antigen-presenting dendritic cells to lymphatic endothelium, through binding to hyaluronan in the leukocyte glycocalyx and inducing formation of transmigratory cups [12]. We have shown that blocking such lymphatic:leukocyte interactions by either monoclonal antibodies or genetic ablation prevents effective primary T-cell responses from being generated in draining lymph nodes [12, 13], again highlighting the vital roles that lymphatics play in immunology.

Currently, I use a wide range of techniques, including microscopy (confocal, spinning disc, multi-photon) and flow cytometry to study interactions and migration of immune cells with lymphatics, studying primary cells in vitro as well as trafficking in transgenic mice. Also, as tumour cells frequently disseminate via lymphatic vessels, I am interested in establishing whether they use similar molecules to those of leukocytes, in order to seed metastases in draining lymph nodes and other more distant sites.

References

1.            Vieira, J.M., et al., The cardiac lymphatic system stimulates resolution of inflammation following myocardial infarction. J Clin Invest, 2018. 128(8): p. 3402-3412.

2.            Alves de Lima, K., J. Rustenhoven, and J. Kipnis, Meningeal Immunity and Its Function in Maintenance of the Central Nervous System in Health and Disease. Annu Rev Immunol, 2020. 38: p. 597-620.

3.            Escobedo, N. and G. Oliver, The Lymphatic Vasculature: Its Role in Adipose Metabolism and Obesity. Cell Metab, 2017. 26(4): p. 598-609.

4.            Baluk, P., et al., Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med, 2007. 204(10): p. 2349-62.

5.            Banerji, S., et al., LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol, 1999. 144(4): p. 789-801.

6.            Johnson, L.A., et al., An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med, 2006. 203(12): p. 2763-77.

7.            Johnson, L.A. and D.G. Jackson, Cell traffic and the lymphatic endothelium. Ann N Y Acad Sci, 2008. 1131: p. 119-33.

8.            Johnson, L.A. and D.G. Jackson, Inflammation-induced secretion of CCL21 in lymphatic endothelium is a key regulator of integrin-mediated dendritic cell transmigration. Int Immunol, 2010. 22(10): p. 839-49.

9.            Johnson, L.A. and D.G. Jackson, The chemokine CX3CL1 promotes trafficking of dendritic cells through inflamed lymphatics. J Cell Sci, 2013. 126(Pt 22): p. 5259-70.

10.         Johnson, L.A. and D.G. Jackson, Control of dendritic cell trafficking in lymphatics by chemokines. Angiogenesis, 2014. 17(2): p. 335-45.

11.         Johnson, L.A., et al., Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem, 2007. 282(46): p. 33671-80.

12.         Johnson, L.A., et al., Dendritic cells enter lymph vessels by hyaluronan-mediated docking to the endothelial receptor LYVE-1. Nat Immunol, 2017. 18(7): p. 762-770.

13.         Teoh, D., et al., Blocking development of a CD8+ T cell response by targeting lymphatic recruitment of APC. J Immunol, 2009. 182(4): p. 2425-31.