The atypical chemokine receptor-2 (ACKR2) is a chemokine decoy receptor that recognises pro-inflammatory CC chemokines. Many studies showed up-regulated inflammation and delayed resolution of inflammatory responses in ACKR2-/- mice. Furthermore, in the absence of ACKR2, lymphatic endothelial cells (LEC) fail to regulate the expression of pro-inflammatory CC chemokines leading to the excessive peri-lymphatic accumulation of leukocytes. As a result, the migration of antigen presenting cells (APC) through lymphatic vessels may be impaired due to lymphatic congestion. In addition, ACKR2 was shown to regulate lymphatic vessel density in the embryonic skin by regulating the proximity of pro-lymphangiogenic macrophages to LEC. Therefore, to address the role of ACKR2 and its significance in 1) APC migration and 2) inflammation-associated lymphangiogenesis, three models of ocular inflammation were used in this work, experimental autoimmune uveoretinitis (EAU), corneal graft rejection and herpes simplex keratitis (HSK). With regard to APC migration, in both EAU and HSK models, this process was fine-tuned to the level of disease in that migration was significantly compromised in ACKR2-/- mice during severe inflammation, but not under mild inflammatory conditions. Furthermore, while the severity of EAU was associated with the migration of APC, this was not so in HSK. In order to study lymphangiogenesis, the transparent avascular cornea provides a good substrate and corneal lymphangiogenesis was studied using both corneal graft model and HSK model. I found that lymphatic vessel density was increased in ACKR2-/- mice compared to wild type mice in corneal graft induced lymphangiogenesis (macrophage mediated), but not altered during early stages of HSK associated lymphangiogenesis (non-macrophage mediated). These findings confirmed that ACKR2 indirectly regulates the process of lymphangiogenesis in a macrophage dependent manner. Although the severity of HSK correlated with the level of lymphangiogenesis, this does not seem to correlate with viral load but rather associated with inflammatory infiltrations in the cornea.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:680996 |
| Date | January 2015 |
| Creators | Yu, Tian |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=229021 |
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