Current Research and Future Plans
Lymphatic vessel biology and function:
Increasing evidence in the literature suggests that the lymphatic system is not an inert but rather plastic system which plays an important role in immunity and inflammation. Having shown a few years ago that inflammatory signals present in a strong adjuvant can induce the remodeling of lymphatic vessels within inflamed lymph node, we are currently investigating further the molecular and cellular events involved in regulating lymphatic vessel remodeling under inflammation. Understanding how lymphatic vessel function may affect the adaptive immune response and the resolution of inflammation is another focus of our work. In this context, we discovered recently an unexpected role for neutrophils in supporting the growth of lymphatic vessels, namely lymphangiogenesis, in peripheral tissue such as the skin and lymph nodes during inflammatory conditions (1). Our work also provides further evidence that lymphatic vessels can modulate the immune response by regulating the trafficking of immune cells including lymphocytes and dendritic cells. Finally, we found that the function of lymphatic vessel is not limited to support the migration of immune cells but it is also critical for the transport of lipids and particularly cholesterol (2). Indeed, we found that in absence of functional lymphatic vessels, cholesterol transport from peripheral tissues back to the liver and bile is significantly impaired, and as a consequence, cholesterol accumulates in peripheral tissues. More importantly, we showed that this lymphatic transport of cholesterol is mediated by the transporter scavenger receptor class B type I on lymphatic endothelial cells which challenges the current view of lymphatic endothelium as a passive barrier. We are now investigating the clinical relevance of our findings.
Atherosclerosis and atherothrombosis:
Atherosclerosis is a systemic disorder of the large and medium-sized arterial vessels, affecting the coronary, cerebral and peripheral circulation. Chronic inflammation is the central pathophysiological mechanism and provides the substrate for occlusive thrombus formation in which platelets are a key player in the initiation and progression of atherothrombosis1. The clinical complications of acute arterial thrombosis, heart attack and stroke, are the most common causes of morbidity and mortality in the industrialized countries including Singapore. Limitations of currently available anti-platelet agents highlight the need to develop additional therapies with novel properties and molecular targets, which will ideally confer maximal protection against cardiovascular events whilst preserving sufficient platelet haemostatic function to minimize bleeding complications. Recently, we have identified a new factor expressed by platelets and we are currently investigating whether it represents a novel molecular target for arterial thrombosis and evaluating its potential and lead clinical applications in close collaboration with Dr Chan, Y.Y from Cardiovascular Research Institute, NUHS.
Project: Neutrophils I
Tan KW, Chong SZ, Wong FH, Evrard M, Tan SM, Keeble J, Kemeny MD, Ng LG, Abastado JP, Angeli V. Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D. Blood. 2013 Nov 21;122(22):3666-77.
Angeli Veronique and Lim Hwee Ying. Emerging role of lymphatic vessels in reverse cholesterol transport. Aging, 2013 June; 5 (6).
Hwee Ying Lim, Chung Hwee Thiam, Kim Pin Yeo, Radjesh Bisoendial, Chung Shii Hii, Kristine CY McGrath, Kar Wai Tan, Alison Heather, J. Steven Jonathan Alexander, Veronique Angeli. Lymphatic vessels are essential for the removal of cholesterol from peripheral tissues by SR-BI-mediated transport of HDL. Cell metabolism. 2013 May; 17(5):671-684.
Tan KW, Yeo KP, Wong H.S., Lim HY, Khoo K.L, Abastado J.P and Véronique Angeli. Expansion of cortical and medullary sinuses restrains lymph node hypertrophy during prolonged inflammation. J. Immunol. 2012 March; 188:4065-4080.
Orna Tal*, Hwee Ying Lim*, Irina Gurevich, Idan Milo, Zohar Shipony, Lai Guan Ng, Veronique Angeli, and Guy Shakhar. Intralymphatic crawling, after docking on immobilized endothelial CCL21, allows DC mobilization from the skin. J. Exp. Med 2011 Sept; 208:: 2141-2153. *: these authors equally contributed
Hwee Ying Lim, Joseph M. Rutkowski, Julie Helft, Sai T. Reddy, Melody A. Swartz, Gwendalyn J. Randolph and Véronique Angeli. Hypercholeserolemic mice exhibit lymphatic vessel dysfunction and degeneration. Am. J. Pathol. 2009 Sept;175(3):1328-37.
Angeli V, Ginhoux F, Llòdra J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, Randolph GJ. B cell driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 2006; 24: 203-215.
Lim Hwee Ying
Yeo Kim Pin