Investigations into mechanisms of macrophage clearance via the lymphatic system during acute inflammation

• Main Author: Bhattacharjee, Shaumick
• Other Authors: Jackson, David
• Published: University of Oxford 2016
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730434

The lymphatic system is an important vascular network with many important roles which include maintaining fluid homeostasis and acting as a conduit for immune surveillance as well as to clear leucocytes from inflammatory zones. Macrophages are one such population that require to be removed from sites of inflammation to restore physiological homeostasis; persistent accumulation of macrophages is seen as a hallmark of chronic inflammation which has severe consequences in health. This thesis is concerned with the mechanisms regulating entry of these myeloid cells into the lymphatic capillaries. In vitro adhesion and transmigration assays revealed macrophages actively adhere and migrate across activated lymphatic endothelial cells (LECs) rapidly although both mechanisms do occur without inflammatory stimulation of the endothelial cells. Unlike neutrophils and dendritic cells, ICAM-1 and VCAM-1 were surprisingly redundant to macrophage transmigration of activated LECs although β2 integrin was significantly involved. A more involved role was found in the LYVE-1-hyaluronan (HA) axis; macrophage derived HA as well as lymphatic hyaluronan receptor LYVE-1 were critical to transmigration but quantitatively minimally involved in adhesion. These findings were consolidated with an in vivo sterile peritonitis model which demonstrated the importance of the receptor to trafficking of macrophages to draining lymph nodes. Furthermore, macrophage expressed CD44 was also shown to be significantly associated in both inflammatory trafficking and transmigration. The results described in this thesis provide novel evidence of the CD44-HA-LYVE-1 axis playing an active role in migration of macrophages via the lymphatics.